Substituted indazole derivatives active as kinase inhibitors

ABSTRACT

Substituted indazole derivatives of formula (I) and pharmaceutically acceptable salts thereof, as defined in the specification; the compounds of the invention may be useful in therapy in the treatment of diseases associated with a deregulated protein kinase activity, like cancer.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application is a continuation of a co-pending applicationhaving U.S. Ser. No. 14/534,617, filed on Nov. 6, 2014, which is acontinuation of a co-pending application having U.S. Ser. No.14/212,256, filed on Mar. 14, 2014, now U.S. Pat. No. 9,029,356, whichis a continuation of a co-pending application having U.S. Ser. No.13/611,679, filed on Sep. 12, 2012, now U.S. Pat. No. 8,673,893, whichis a continuation of the application having U.S. Ser. No. 12/668,745,filed on Feb. 8, 2010, now U.S. Pat. No. 8,299,057, which is a 371 ofInternational application having Serial No. PCT/EP08/058861, filed onJul. 8, 2008, which claims benefit of European Patent Application No.07112881.3, filed on Jul. 20, 2007, the contents of all of which areincorporated herein by reference.

INCORPORATION BY REFERENCE OF SEQUENCE LISTING

The Sequence Listing in the ASCII text file, named as24846_sequencelisting.txt of 2 KB, created on May 25, 2010, andsubmitted to the United States Patent and Trademark Office via EFS-Web,is incorporated herein by reference.

BACKGROUND OF THE INVENTION

The present invention relates to certain substituted indazole compounds,which modulate the activity of protein kinases. The compounds of thisinvention are therefore useful in treating diseases caused byderegulated protein kinase activity. The present invention also providesmethods for preparing these compounds, pharmaceutical compositionscomprising these compounds, and methods of treating diseases utilizingpharmaceutical compositions comprising these compounds.

The malfunctioning of protein kinases (PKs) is the hallmark of numerousdiseases. A large share of the oncogenes and proto-oncogenes involved inhuman cancers encode for PKs. The enhanced activities of PKs are alsoimplicated in many non-malignant diseases, such as benign prostatehyperplasia, familial adenomatosis, polyposis, neuro-fibromatosis,psoriasis, vascular smooth cell proliferation associated withatherosclerosis, pulmonary fibrosis, arthritis glomerulonephritis andpost-surgical stenosis and restenosis.

PKs are also implicated in inflammatory conditions and in themultiplication of viruses and parasites. PKs may also play a major rolein the pathogenesis and development of neurodegenerative disorders.

For a general reference to PKs malfunctioning or deregulation see, forinstance, Current Opinion in Chemical Biology 1999, 3, 459-465. A subsetof PK is a group of membrane receptors with intrinsic protein-tyrosinekinase activity (RPTK). Upon binding of grow factors, RPTKs becomeactivated and phosphorylate themselves and a series of substrates in thecytoplasm. Through this mechanism, they can transduce intracellularsignalings for proliferation, differentiation or other biologicalchanges. Structural abnormalities, over-expression and activation ofRTPKs are frequently observed in human tumors, suggesting thatconstitutive ignition of the signal transduction leading to cellproliferation can result in malignant transformation. Anaplasticlymphoma kinase (ALK) is a tyrosine kinase receptor belonging to theinsulin receptor subfamily of RTKs: the ALK gene is located on cromosome2 and is expressed mainly in neuronal cells, especially duringdevelopment. The ALK gene is involved in a balanced chromosomaltranslocation with the Nucleophosmin (NPM) gene on cromosome 5 in alarge subset of Anaplastic Large Cell Lymphomas (ALCL). In the ALK+ALCL,as a result of the translocation, the NPM ubiquitous promoter drives anectopic expression of the fusion protein in which the NPM moietydimerizes and the ALK kinase domain undergoes auto-phosphorylation andbecomes constitutively active.

Many data from the literature have demonstrated that the NPM-ALK fusionprotein has a strong oncogenic potential and its ectopic expression isresponsible for cellular transformation. Moreover, the constitutiveexpression of human NPM-ALK in mouse T-cell lymphocytes is sufficientfor the development of lymphoid neoplasia in transgenic animals with ashort period of latency.

ALCL is a defined disease characterized by the surface expression of theCD30 antigen (Ki-1), and accounts for 2% of adult and 13% of pediatricnon-Hodgkin's lymphomas, affecting predominantly young male patients.ALK+ALCL accounts for 70% of all ALCLs and is an aggressive disease withsystemic signs, and frequent extranodal involvement (bone marrow, skin,bone, soft tissues).

About 15-20% of ALK-expressing ALCLs were found to bear a differentchromosomal translocation, involving the cytoplasmic portion of ALK,with different N-terminal moieties, all resulting in constitutiveactivation of the ALK kinase domain. Moreover, cell lines establishedfrom solid tumors of ectodermal origin like melanomas, breastcarcinomas, as well as neuroblastomas, glioblastomas, Ewings sarcomas,retinoblastomas, were found to express the ALK receptor.

In conclusion, interfering with the ALK signalling likely represents aspecific and effective way to block tumor cell proliferation in ALCL andpossibly other indications.

The insulin-like growth factor 1 receptor (IGF-1R, IGF1R) is also amember of the insulin receptor subfamily of RTKs.

There exist several lines of evidence suggesting that IGF-1R signalingcan contribute to tumorigenesis, and that interfering with IGF-1Rfunction represents a valid therapeutic option in cancer. For anoverview of IGFs and IGF-1R signalling, physiological function, anddetailed description of the evidence supporting involvement of thissystem in human cancer that is summarised above, as well as in otherpathologies, the reader is directed to the many reviews on the subjectand references contained therein, for example Baserga R. et al, BiochimBiophys Acta vol. 1332, pages F105-F126, 1997; Khandwala H. M. et al,Endocr Rev vol. 21, pages 215-44, 2000; Le Roith D. et al, Endocr Revvol. 22, pages 53-74, 2001; Valentinis B. et al, Mol Pathol vol. 54,pages 133-7, 2001; Wang Y. et al, Curr Cancer Drug Targets vol. 2, pages191-207, 2002; Laron, Z. J Clin Endocrinol Metab vol. 89, pages1031-1044, 2004; Hofmann F et al, Drug Discov Today vol. 10, pages1041-7, 2005.

SUMMARY OF THE INVENTION

3-Amino and 3-acylamino indazole derivatives for the treatment ofneurodegenerative diseases, cerebrovascular accidents, obesity,cardiovascular diseases and cancer are disclosed in WO2006003276,WO2004022544 and WO 2003078403 in the name of Aventis Pharma SA.

Indazolylamide derivatives for the treatment of diabetes,neurodegenerative conditions such as Alzheimer's disease and Parkinson'sdisease are disclosed in WO2003051847 in the name of SmithKline BeechamP. L. C.

Indazole derivatives for the treatment of tumor disease, viral disease,immunosuppression in transplantation, cystic fibrosis and diseasesassociated with angiogenesis are disclosed in WO2008003396 in the nameof Merck GMBH. Despite these developments, there is still a need formore effective agents for the treatment of such diseases

We have now discovered that a series of indazoles are potent proteinkinase inhibitors and are thus useful in anticancer therapy.

Accordingly, a first object of the present invention is to provide asubstituted indazole compound represented by formula (I),

wherein:

X is —CH₂—, —CH(OH)—, —CH(OR′)— or —C(R′R″)—, wherein:

R′ is an optionally further substituted straight or branched C₁-C₆ alkyland R″ is hydrogen or an optionally further substituted straight orbranched C₁-C₆ alkyl;

Ar is aryl or heteroaryl optionally substituted with one or moresubstituents independently selected from halogen, C₂-C₆ alkenyl, C₂-C₆alkynyl, cyano, nitro, NHCOR4, COR4, NR5R6, NR5COR4, OR7, SR7, SOR10,SO₂R10, NHSOR10, NHSO₂R10, R8R9N—C₁-C₆ alkyl, R8O—C₁-C₆ alkyl, anoptionally further substituted straight or branched C₁-C₆ alkyl, C₃-C₆cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein:

R4 is hydrogen, C₂-C₆ alkenyl, C₂-C₆ alkynyl, NR5R6, OR7, SR7,R8R9N—C₁-C₆ alkyl, R8O—C₁-C₆ alkyl, an optionally further substitutedstraight or branched C₁-C₆ alkyl, C₃-C₆ cycloalkyl, heterocyclyl, arylor heteroaryl;

R5 and R6 are independently hydrogen, C₂-C₆ alkenyl, C₂-C₆ alkynyl,R8R9N—C₂-C₆ alkyl, R8O—C₂-C₆ alkyl, an optionally further substitutedstraight or branched C₁-C₆ alkyl, C₃-C₆ cycloalkyl, heterocyclyl, arylor heteroaryl, or R5 and R6, taken together with the nitrogen atom towhich they are bonded, may form an optionally substituted heterocyclylgroup;

R7 is hydrogen, C₂-C₆ alkenyl, C₂-C₆ alkynyl, COR4, SOR10, SO₂R10,R8R9N—C₂-C₆ alkyl, R8O—C₂-C₆ alkyl, an optionally further substitutedstraight or branched C₁-C₆ alkyl, C₃-C₆ cycloalkyl, heterocyclyl, arylor heteroaryl, wherein R4 is as defined above;

R8 and R9 are independently hydrogen, C₂-C₆ alkenyl, C₂-C₆ alkynyl,COR4, an optionally further substituted straight or branched C₁-C₆alkyl, C₃-C₆ cycloalkyl, heterocyclyl, aryl or heteroaryl, or R8 and R9,taken together with the nitrogen atom to which they are bonded, may forman optionally substituted heterocyclyl group, wherein R4 is as definedabove;

R10 is hydrogen, C₂-C₆ alkenyl, C₂-C₆ alkynyl, NR5R6, OR7, R8R9N—C₁-C₆alkyl, R8O—C₁-C₆ alkyl, an optionally further substituted straight orbranched C₁-C₆ alkyl, C₃-C₆ cycloalkyl, heterocyclyl, aryl orheteroaryl, wherein R5, R6, R7, R8 and R9 are as defined above;

R is an optionally substituted straight or branched C₁-C₆ alkyl, C₃-C₆cycloalkyl, heterocyclyl, aryl or heteroaryl;

R1, R2 and R3 are independently hydrogen, halogen, nitro, an optionallysubstituted straight or branched C₁-C₆ alkyl, NR5R6, or OR7, wherein R5,R6 and R7 are as defined above;

or isomers, tautomers, prodrugs or pharmaceutically acceptable saltthereof.

The present invention also provides methods of synthesizing thesubstituted indazole derivatives of formula (I) prepared through aprocess consisting of standard synthetic transformations.

The present invention also provides a method for treating diseasescaused by and/or associated with deregulated protein kinase activity,particularly PLK family, protein kinase C in different isoforms, Met,PAK-4, PAK-5, ZC-1, STLK-2, DDR-2, Aurora 1, Aurora 2, Bub-1, Chk1,Chk2, HER2, raf1, MEK1, MAPK, EGF-R, PDGF-R, FGF-R, FLT3, JAK2, IGF-R,ALK, PI3K, weel kinase, Src, Abl, Akt, MAPK, ILK, MK-2, IKK-2, Cdc7,Nek, Cdk/cyclin kinase family, more particularly Aurora 2, IGF-1R andALK activity, and further more particularly ALK activity, whichcomprises administering to a mammal in need thereof an effective amountof a substituted indazole compound represented by formula (I) as definedabove.

A preferred method of the present invention is to treat a disease causedby and/or associated with dysregulated protein kinase activity selectedfrom the group consisting of cancer and cell proliferative disorders.

Another preferred method of the present invention, is to treat specifictypes of cancer including carcinoma, squamous cell carcinoma,hematopoietic tumors of myeloid or lymphoid lineage, tumors ofmesenchymal origin, tumors of the central and peripheral nervous system,melanoma, seminoma, teratocarcinoma, osteosarcoma, xerodermapigmentosum, keratocanthomas, thyroid follicular cancer and Kaposi'ssarcoma.

Another preferred method of the present invention, is to treat specifictypes of cancer such as, but not restricted to, breast cancer, lungcancer, colorectal cancer, prostate cancer, ovarian cancer, endometrialcancer, gastric cancer, clear cell renal cell carcinoma, uveal melanoma,multiple myeloma, rhabdomyosarcoma, Ewing's sarcoma, Kaposi's sarcoma,and medulloblastoma.

Another preferred method of the present invention, is to treatALK+Anaplastic Large Cell Lymphomas (ALCL) and possibly otherindications in which the ALK activity might play a role, likeNeuroblastoma, Rhabdomyosarcoma, Glioblastoma, InflammatoryMyofibroblasticTumor, and some kind of Melanomas, Breast Carcinomas,Ewings sarcomas, Retinoblastomas and Non Small Cell Lung Carcinomas(NSCLC).

Another preferred method of the present invention, is to treat cellproliferative disorders such as, but not restricted to, benign prostatehyperplasia, familial adenomatosis polyposis, neuro-fibromatosis,psoriasis, atherosclerosis and conditions involving vascular smoothmuscle proliferation or neointimal formation such as restenosisfollowing angioplasty or surgery, pulmonary fibrosis, arthritis,glomerulonephritis, retinopathies including diabetic and neonatalretinopathies and age related macular degeneration, graft vesseldisease, such as can occur following vessel or organ transplantation,acromegaly and disorders secondary to acromegaly as well as otherhypertrophic conditions in which IGF/IGF-1R signalling is implicated,such as fibrotic lung disease, pathologies related to chronic or acuteoxidative stress or hyperoxia induced tissue damage, and metabolicdisorders in which elevated IGF levels or IGF-1R activity areimplicated, such as obesity.

In addition, the method of the present invention also provides tumorangiogenesis and metastasis inhibition.

In a further preferred embodiment, the method of the present inventionfurther comprises subjecting the mammal in need thereof to a radiationtherapy or chemotherapy regimen in combination with at least onecytostatic or cytotoxic agent.

Moreover the invention provides a method for inhibiting the activity ALKprotein which comprises contacting the said protein with an effectiveamount of a compound of formula (I).

The present invention also provides a pharmaceutical compositioncomprising one or more compounds of formula (I) or a pharmaceuticallyacceptable salt thereof and a pharmaceutically acceptable excipient,carrier or diluent.

The present invention further provides a pharmaceutical compositioncomprising a compound of formula (I) in combination with one or morechemotherapeutic agents or radiotherapy. Such agents can include, butare not limited to, antihormonal agents such as antiestrogens,antiandrogens and aromatase inhibitors, topoisomerase I inhibitors,topoisomerase II inhibitors, agents that target microtubules,platin-based agents, alkylating agents, DNA damaging or intercalatingagents, antineoplastic antimetabolites, other kinase inhibitors, otheranti-angiogenic agents, inhibitors of kinesins, therapeutic monoclonalantibodies, inhibitors of mTOR, histone deacetylase inhibitors, famesyltransferase inhibitors, and inhibitors of hypoxic response.

Additionally, the invention provides a product or kit comprising acompound of formula (I) or a pharmaceutically acceptable salt thereof,as defined above, or pharmaceutical compositions thereof and one or morechemotherapeutic agents, as a combined preparation for simultaneous,separate or sequential use in anticancer therapy.

In yet another aspect the invention provides a compound of formula (I)or a pharmaceutically acceptable salt thereof, as defined above, for useas a medicament. Moreover the invention provides the use of a compoundof formula (I) or a pharmaceutically acceptable salt thereof, as definedabove, in the manufacture of a medicament with antitumor activity.

Finally, the invention provides a compound of formula (I) or apharmaceutically acceptable salt thereof, as defined above, for use in amethod of treating cancer.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of formula (I) may have one or more asymmetric centres,and may therefore exist as individual optical isomers or racemicmixtures. Accordingly, all the possible isomers, and their mixtures, ofthe compounds of formula (I) are within the scope of the presentinvention.

Derivatives of compounds of formula (I) originating from metabolism in amammal, and the pharmaceutically acceptable bio-precursors (otherwisereferred to as pro-drugs) of the compounds of formula (I) are alsowithin the scope of the present invention.

In addition to the above, as known to those skilled in the art, theunsubstituted nitrogen on the pyrazole ring of the compounds of formula(I) rapidly equilibrates in solution to form a mixture of tautomers, asdepicted below:

wherein X, Ar, R, R1, R2 and R3 are as defined above.

Accordingly, in the present invention, where only one tautomer isindicated for the compounds of formula (I), the other tautomer (Ia) isalso within the scope of the present invention, unless specificallynoted otherwise.

The general terms as used herein, unless otherwise specified, have themeaning reported below.

The term “straight or branched C₁-C₆ alkyl” refers to a saturatedaliphatic hydrocarbon radical, including straight chain and branchedchain groups of from 1 to 6 carbon atoms, e.g. methyl, ethyl, propyl,2-propyl, n-butyl, iso-butyl, tert-butyl, pentyl and the like. The alkylgroup may be substituted or unsubstituted. When substituted, thesubstituent groups are preferably one to three, independently selectedfrom the group consisting of halogen, C₂-C₆ alkenyl, C₂-C₆ alkynyl,cyano, nitro, NHCOR4, COR4, NR5R6, NR5COR4, OR7, SR7, SOR10, SO₂R10,NHSOR10, NHSO₂R10, R8R9N—C₁-C₆ alkyl, R8O—C₁-C₆ alkyl, an optionallyfurther substituted C₃-C₆ cycloalkyl, heterocyclyl and aryl, wherein R4,R5, R6, R7, R8, R9 and R10 are as defined above.

The term “C₃-C₆ cycloalkyl” refers to a 3- to 6-membered all-carbonmonocyclic ring, which may contain one or more double bonds but does nothave a completely conjugated π-electron system. Examples of cycloalkylgroups, without limitation, are cyclopropyl, cyclobutyl, cyclopentyl,cyclopentenyl, cyclohexyl, cyclohexenyl and cyclohexadienyl. Acycloalkyl group may be substituted or unsubstituted. When substituted,the substituent groups are preferably one or two substituents,independently selected from the group consisting of halogen, C₂-C₆alkenyl, C₂-C₆ alkynyl, cyano, nitro, NHCOR4, COR4, NR5R6, NR5COR4, OR7,SR7, SOR10, SO₂R10, NHSOR10, NHSO₂R10, R8R9N—C₁-C₆ alkyl, R8O—C₁-C₆alkyl, an optionally further substituted straight or branched C₁-C₆alkyl, C₃-C₆ cycloalkyl, heterocyclyl and aryl, wherein R4, R5, R6, R7,R5, R9 and R10 are as defined above.

The term “heterocyclyl” refers to a 3- to 7-membered, saturated orpartially unsaturated carbocyclic ring where one or more carbon atomsare replaced by heteroatoms such as nitrogen, oxygen and sulfur. Notlimiting examples of heterocyclyl groups are, for instance, oxiranyl,aziridinyl, oxetanyl, azetidinyl, tetrahydrofuranyl, dihydrofuranyl,tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl,pyranyl, dihydropyranyl, tetrahydropyranyl, tetrahydrothiopyranyl,piperidinyl, pyrazolinyl, isoxazolidinyl, isoxazolinyl, thiazolidinyl,thiazolinyl, isothiazolinyl, dioxanyl, piperazinyl, morpholinyl,thiomorpholinyl, examethyleneiminyl, homopiperazinyl and the like. Aheterocyclyl group may be substituted or unsubstituted.

When substituted, the substituent groups are preferably one or twosubstituents, independently selected from the group consisting ofhalogen, C₂-C₆ alkenyl, C₂-C₆ alkynyl, cyano, nitro, NHCOR4, COR4,NR5R6, NR5COR4, OR7, SR7, SOR10, SO₂R10, NHSOR10, NHSO₂R10, R8R9N—C₁-C₆alkyl, R8O—C₁-C₆ alkyl, an optionally further substituted straight orbranched C₁-C₆ alkyl, C₃-C₆ cycloalkyl, heterocyclyl and aryl, whereinR4, R5, R6, R7, R8, R9 and R10 are as defined above.

The term “aryl” refers to a mono-, bi- or poly-carbocyclic hydrocarbonwith from 1 to 4 ring systems, optionally further fused or linked toeach other by single bonds, wherein at least one of the carbocyclicrings is “aromatic”, wherein the term “aromatic” refers to completelyconjugated pi-electron bond system. Non limiting examples of such arylgroups are phenyl, α- or β-naphthyl or biphenyl groups.

The term “heteroaryl” refers to aromatic heterocyclic rings, typically5- to 7-membered heterocycles with from 1 to 3 heteroatoms selectedamong N, O or S; the heteroaryl ring can be optionally further fused orlinked to aromatic and non-aromatic carbocyclic and heterocyclic rings.Not limiting examples of such heteroaryl groups are, for instance,pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, imidazolyl,thiazolyl, isothiazolyl, pyrrolyl, phenyl-pyrrolyl, furyl, phenyl-furyl,oxazolyl, isoxazolyl, pyrazolyl, thienyl, benzothienyl, isoindolinyl,benzoimidazolyl, quinolinyl, isoquinolinyl, 1,2,3-triazolyl,1-phenyl-1,2,3-triazolyl, 2,3-dihydroindolyl, 2,3-dihydrobenzofuranyl,2,3-dihydrobenzothiophenyl; benzopyranyl, 2,3-dihydrobenzoxazinyl,2,3-dihydroquinoxalinyl and the like.

The aryl and heteroaryl groups can be optionally substituted by one ormore, preferably one, two or three substituents independently selectedfrom halogen, C₂-C₆ alkenyl, C₂-C₆ alkynyl, cyano, nitro, NHCOR4, COR4,NR5R6, NR5COR4, OR7, SR7, SOR10, SO₂R10, NHSOR10, NHSO₂R10, R8R9N—C₁-C₆alkyl, R8O—C₁-C₆ alkyl, an optionally further substituted straight orbranched C₁-C₆ alkyl, C₃-C₆ cycloalkyl, heterocyclyl and aryl, whereinR4, R5, R6, R7, R8, R9 and R10 are as defined above.

The term “halogen” indicates fluorine, chlorine, bromine or iodine.

The term “C₂-C₆ alkenyl” indicates an aliphatic C₂-C₆ hydrocarbon chaincontaining at least one carbon-carbon double bond and which can bestraight or branched. Representative examples include, but are notlimited to, ethenyl, 1-propenyl, 2-propenyl, 1- or 2-butenyl, and thelike.

The term “C₂-C₆ alkynyl” indicates an aliphatic C₂-C₆ hydrocarbon chaincontaining at least one carbon-carbon double bond and which can bestraight or branched. Representative examples include, but are notlimited to, ethynyl, 1-propynyl, 2-propynyl, 1- or 2-butynyl, and thelike.

The term “cyano” indicates a —CN residue.

The term “nitro” indicates a —NO₂ group.

The term “pharmaceutically acceptable salt” of compounds of formula (I)refers to those salts that retain the biological effectiveness andproperties of the parent compound. Such salts include acid additionsalts with inorganic acids such as hydrochloric, hydrobromic, nitric,phosphoric, sulfuric, perchloric acid and the like, or with organicacids such as acetic, trifluoroacetic, propionic, glycolic, lactic, (D)or (L) malic, maleic, methanesulfonic, ethanesulfonic, benzoic,p-toluenesulfonic, salicylic, cinnamic, mandelic, tartaric, citric,succinic, malonic acid and the like; salts formed when an acidic protonpresent in a compound of formula (I) is either replaced by a metal ion,e.g., an alkali metal ion such as sodium or potassium, or an alkalineearth ion such as calcium or magnesium, or coordinates with an organicbase such as ethanolamine, diethanolamine, triethanolamine,tromethamine, N-methylglucamine, and the like.

Compounds of formula (I) wherein X is —CH₂—, are represented by thegeneral formula (I_(A)):

Compounds of formula (I) wherein X is —CH(OH)—, are represented by thegeneral formula (I_(B)):

Compounds of formula (I) wherein X is —CH(OR′)—, are represented by thegeneral formula (I_(C)):

Compounds of formula (I) wherein X is —C(R′R″)—, are represented by thegeneral formula (I_(D)):

A preferred class of compounds of formula (I) are the compounds wherein:

X is —CH₂—, —CH(OH)—, —CH(OR′)— or —C(R′R″)—, wherein R′ is C₁-C₃ alkyland R″ is hydrogen or C₁-C₃ alkyl;

R is an optionally substituted C₃-C₆ cycloalkyl, heterocyclyl, aryl orheteroaryl, and

R1, R2 and R3 are independently hydrogen, halogen or hydroxy.

Another preferred class of compounds of formula (I) are the compoundswherein:

X is —CH₂—, —CH(OH)—, —CH(OR′)— or —C(R′R″)—, wherein R′ is methyl andR″ is hydrogen or methyl, and

R1, R2 and R3 are hydrogen.

A further preferred class of compounds of formula (I) are the compoundswherein R is an optionally substituted aryl or heteroaryl.

A more preferred class of compounds of formula (I) are the compoundswherein Ar is a group of formula:

wherein Ra, Rb and Rc are independently hydrogen, halogen, C₂-C₆alkenyl, C₂-C₆ alkynyl, cyano, nitro, NHCOR4, COR4, NR5R6, NR5COR4, OR7,SR7, SOR10, SO₂R10, NHSOR10, NHSO₂R10, R8R9N—C₁-C₆ alkyl, R8O—C₁-C₆alkyl, an optionally further substituted straight or branched C₁-C₆alkyl, C₃-C₆ cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein R4,R5, R6, R7, R8, R9 and R10 are as defined above and

R is an optionally substituted aryl.

A further more preferred class of compounds of formula (I) are thecompounds wherein:

Ar is a group of formula:

wherein Ra and Rb are as defined above.

A most preferred class of compounds of formula (I) are the compoundswherein:

Ar is a group of formula:

wherein Ra is hydrogen, halogen, nitro, NHCOR4 or NR5R6 and Rb ishydrogen, nitro, NR5R6, OR7 or R8R9N—C₁-C₆ alkyl wherein R4, R5, R6, R7,R8 and R9 are as defined above.

Specific compounds (cpd.) of the invention are listed below:

-   1.    N-(5-benzyl-1H-indazol-3-yl)-4-(4-methyl-piperazin-1-yl)-benzamide;-   2.    N-[5-(3-fluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-benzamide;-   3.    N-[5-(2,5-difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)benzamide;-   4.    N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)benzamide;-   5.    N-[5-(3-fluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-nitrobenzamide;-   6.    N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-nitro-benzamide;-   7.    2-Amino-N-[5-(3-fluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-benzamide;-   8.    2-Amino-N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-benzamide;-   9.    N-[5-(3-fluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;-   10.    N-[5-(2,5-difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;-   11.    N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;-   12.    N-[5-(3-fluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(1-methyl-piperidin-4-ylamino)-benzamide;-   13.    N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(1-methyl-piperidin-4-ylamino)-benzamide;-   14.    N-[5-(3-fluoro-benzyl)-1H-indazol-3-yl]-2-(2-methoxy-1-methoxymethyl-ethylamino)-4-(4-methyl-piperazin-1-yl)-benzamide:-   15.    N-[5-(2,5-difluoro-benzyl)-1H-indazol-3-yl]-2-(2-methoxy-1-methoxymethyl-ethylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;-   16.    N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-2-(2-methoxy-1-methoxymethyl-ethylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;-   17.    2-cyclohexylamino-N-[5-(3-fluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-benzamide;-   18.    2-cyclohexylamino-N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-benzamide;-   19.    N-[5-(3-fluoro-benzyl)-1H-indazol-3-yl]-2-(4-hydroxy-cyclohexylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;-   20.    N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-2-(4-hydroxy-cyclohexylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;-   21.    N-[5-(3-fluoro-benzyl)-1H-indazol-3-yl]-2-isobutylamino-4-(4-methyl-piperazin-1-yl)-benzamide;-   22.    N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-2-isobutylamino-4-(4-methyl-piperazin-1-yl)-benzamide;-   23.    2-benzylamino-N-[5-(3-fluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-benzamide;-   24.    2-benzylamino-N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-benzamide;-   25.    N-[5-(3-fluoro-benzyl)-1H-indazol-3-yl]-2-(2-methoxy-ethylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;-   26.    N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-2-(2-methoxy-ethylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;-   27.    N-[5-(3-fluoro-benzyl)-1H-indazol-3-yl]-2-(2-methoxy-1-methyl-ethylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;-   28.    N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-2-(2-methoxy-1-methyl-ethylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;-   29.    N-[5-(3-fluoro-benzyl)-1H-indazol-3-yl]-2-((S)-2-methoxy-1-methyl-ethylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;-   30.    N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-2-((S)-2-methoxy-1-methyl-ethylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;-   31.    N-[5-(3-fluoro-benzyl)-1H-indazol-3-yl]-2-((R)-2-methoxy-1-methyl-ethylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;-   32.    N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-2-((R)-2-methoxy-1-methyl-ethylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;-   33.    N-[5-(3-fluoro-benzyl)-1H-indazol-3-yl]-2-(2-methoxy-1,1-dimethyl-ethylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;-   34.    N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-2-(2-methoxy-1,1-dimethyl-ethylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;-   35.    N-[5-(3-fluoro-benzyl)-1H-indazol-3-yl]-2-(3-methoxy-propylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;-   36.    N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-2-(3-methoxy-propylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;-   37.    N-[5-(3-fluoro-benzyl)-1H-indazol-3-yl]-2-(2-fluoro-ethylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;-   38.    N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-2-(2-fluoro-ethylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;-   39.    N-[5-(3-fluoro-benzyl)-1H-indazol-3-yl]-2-(3-fluoro-propylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;-   40.    N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-2-(3-fluoro-propylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;-   41.    N-[5-(3-fluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-phenylamino-benzamide;-   42.    N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-phenylamino-benzamide;-   43. 1H-pyrrole-2-carboxylic acid    [2-[5-(3-fluoro-benzyl)-1H-indazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide;-   44. 1H-pyrrole-2-carboxylic acid    [2-[5-(3,5-difluoro-benzyl)-1H-indazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide;-   45. 1H-pyrrole-3-carboxylic acid    [2-[5-(3-fluoro-benzyl)-1H-indazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide;-   46. 1H-pyrrole-3-carboxylic acid    [2-[5-(3,5-difluoro-benzyl)-1H-indazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide;-   47.    N-[5-(3-fluoro-benzyl)-1H-indazol-3-yl]-2-methanesulfonylamino-4-(4-methyl-piperazin-1-yl)-benzamide;-   48.    N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-2-methanesulfonylamino-4-(4-methyl-piperazin-1-yl)-benzamide;-   49.    2-fluoro-N-[5-(3-fluoro-benzyl)-1H-indazol-3-yl]-5-(tetrahydro-pyran-4-ylamino)-benzamide;-   50.    N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-2-fluoro-5-(tetrahydro-pyran-4-ylamino)-benzamide;-   51.    2-fluoro-N-[5-(3-fluoro-benzyl)-1H-indazol-3-yl]-5-(2-methoxy-ethylamino)-benzamide;-   52.    N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-2-fluoro-5-(2-methoxy-ethylamino)-benzamide;-   53.    4-[(3-dimethylamino-propyl)-methyl-amino]-N-[5-(3-ethoxy-benzyl)-1H-indazol-3-yl]-2-nitro-benzamide;-   54.    2-amino-4-[(3-dimethylamino-propyl)-methyl-amino]-N-[5-(3-ethoxy-benzyl)-1H-indazol-3-yl]-benzamide;-   55.    N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-[(3-dimethylamino-propyl)-methyl-amino]-2-(tetrahydro-pyran-4-ylamino)-benzamide;-   56.    N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-[(3-dimethylamino-propyl)-methyl-amino]-2-(2-methoxy-1-methoxymethyl-ethylamino)-benzamide;-   57.    2-amino-N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-[(3-dimethylamino-propyl)-methyl-amino]-benzamide;-   58.    N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-[(3-dimethylamino-propyl)-methyl-amino]-benzamide;-   59.    N-[5-(3,5-difluoro-benzyl)-1-indazol-3-yl]-4-[(3-dimethylamino-propyl)-methyl-amino]-2-nitro-benzamide;-   60.    N-{5-[(3,5-difluoro-phenyl)-hydroxy-methyl]-1H-indazol-3-yl}-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;-   61.    N-{5-[(3,5-difluoro-phenyl)-hydroxy-methyl]-1H-indazol-3-yl}-2-(2-methoxy-1-methoxymethyl-ethylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;-   62.    N-{5-[(3,5-difluoro-phenyl)-hydroxy-methyl]-1H-indazol-3-yl}-4-(4-methyl-piperazin-1-yl)-benzamide;-   63.    N-{5-[(3,5-difluoro-phenyl)-hydroxy-methyl]-1H-indazol-3-yl}-2-(2-methoxy-ethylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;-   64.    N-{5-[(3,5-difluoro-phenyl)-hydroxy-methyl]-1H-indazol-3-yl}-2-(3-methoxy-propylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;-   65.    N-{5-[(3,5-difluoro-phenyl)-hydroxy-methyl]-1H-indazol-3-yl}-2-(2-methoxy-1,1-dimethyl-ethylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;-   66.    N-{5-[(3,5-difluoro-phenyl)-hydroxy-methyl]-1H-indazol-3-yl}-2-(2-fluoro-ethylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;-   67.    N-{5-[(3-ethoxy-phenyl)-hydroxy-methyl]-1H-indazol-3-yl}-4-(4-methyl-piperazin-1-yl)-2-nitro-benzamide;-   68.    N-{5-[(3,5-difluoro-phenyl)-methoxy-methyl]-1H-indazol-3-yl}-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;-   69.    N-{5-[(3,5-difluoro-phenyl)-methoxy-methyl]-1H-indazol-3-yl}-2-(2-methoxy-1-methoxymethyl-ethylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;-   70.    N-{5-[(3,5-difluoro-phenyl)-methoxy-methyl]-1H-indazol-3-yl}-4-(4-methyl-piperazin-1-yl)-benzamide;-   71.    N-{5-[(3,5-difluoro-phenyl)-methoxy-methyl]-1H-indazol-3-yl}-2-(2-methoxy-ethylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;-   72.    N-{5-[(3,5-difluoro-phenyl)-methoxy-methyl]-1H-indazol-3-yl}-2-(3-methoxy-propylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;-   73.    N-{5-[(3,5-difluoro-phenyl)-methoxy-methyl]-1H-indazol-3-yl}-2-(2-methoxy-1,1-dimethyl-ethylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;-   74.    N-{5-[(3,5-difluoro-phenyl)-methoxy-methyl]-1H-indazol-3-yl}-2-(2-fluoro-ethylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;-   75.    N-{5-[1-(3,5-difluoro-phenyl)-ethyl]-1H-indazol-3-yl}-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;-   76.    N-{5-[1-(3,5-difluoro-phenyl)-ethyl]-1H-indazol-3-yl}-2-(2-methoxy-1-methoxymethyl-ethylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;-   77.    N-{5-[(3,5-difluoro-phenyl)-ethyl]-1H-indazol-3-yl}-4-(4-methyl-piperazin-1-yl)-benzamide;-   78.    N-{5-[(3,5-difluoro-phenyl)-ethyl]-1H-indazol-3-yl}-2-(2-methoxy-ethylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;-   79.    N-({5-[(3,5-difluoro-phenyl)-ethyl]-1H-indazol-3-yl}-2-(3-methoxy-propylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;-   80.    N-{5-[(3,5-difluoro-phenyl)-ethyl]-1H-indazol-3-yl}-2-(2-methoxy-1,1-dimethyl-ethylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;-   81.    N-{5-[(3,5-difluoro-phenyl)-ethyl]-1H-indazol-3-yl}-2-(2-fluoro-ethylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;-   82.    N-{5-[1-(3,5-difluoro-phenyl)-1-methyl-ethyl]-1H-indazol-3-yl}-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;-   83.    N-{5-[1-(3,5-difluoro-phenyl)-1-methyl-ethyl]-1H-indazol-3-yl}-2-(2-methoxy-1-methoxymethyl-ethylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;-   84.    N-{5-[1-(3,5-difluoro-phenyl)-1-methyl-ethyl]-1H-indazol-3-yl}-4-(4-methyl-piperazin-1-yl)-benzamide;-   85.    N-{5-[1-(3,5-difluoro-phenyl)-1-methyl-ethyl]-1H-indazol-3-yl}-2-(2-methoxy-ethylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;-   86.    N-{5-[1-(3,5-difluoro-phenyl)-1-methyl-ethyl]-1H-indazol-3-yl}-2-(3-methoxy-propylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;-   87.    N-{5-[1-(3,5-difluoro-phenyl)-1-methyl-ethyl]-1H-indazol-3-yl}-2-(2-methoxy-1,1-dimethyl-ethylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;-   88.    N-{5-[1-(3,5-difluoro-phenyl)-1-methyl-ethyl]-1H-indazol-3-yl}-2-(2-fluoro-ethylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;-   89.    N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-1,4-diazepan-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide;-   90.    N-[5-(3,5-Difluoro-benzyl)-1H-indazol-3-yl]-4-[(2-dimethylamino-ethyl)-methyl-amino]-2-(tetrahydro-pyran-4-ylamino)-benzamide;-   91.    N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-[4-(dimethylamino)piperidin-1-yl]-2-(tetrahydro-2H-pyran-4-ylamino)benzamide;-   92.    N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-[(2S)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]-2-(tetrahydro-2H-pyran-4-ylamino)benzamide;-   93.    N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-3-(4-methylpiperazin-1-yl)benzamide;-   94.    N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-{[(2S)-1-methylpyrrolidin-2-yl]methoxy}-2-(tetrahydro-2H-pyran-4-ylamino)benzamide;-   95.    N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-[(1-methylpiperidin-4-yl)oxy]-2-(tetrahydro-2H-pyran-4-ylamino)benzamide;-   96.    N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-[2-(dimethylamino)ethoxy]-2-(tetrahydro-2H-pyran-4-ylamino)benzamide;-   97.    N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-{[(3S)-1-methylpyrrolidin-3-yl]oxy}-2-(tetrahydro-2H-pyran-4-ylamino)benzamide;-   98.    N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide;-   99.    N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methylpiperazin-1-yl)-2-{[cis-4-(trifluoromethyl)cyclohexyl]amino}benzamide;-   100.    N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methylpiperazin-1-yl)-2-{[trans-4-(trifluoromethyl)cyclohexyl]amino}benzamide;-   101.    N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-2-fluoro-4-(4-methylpiperazin-1-yl)benzamide;-   102.    N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-1-(piperidin-4-yl)-1H-pyrazole-4-carboxamide;-   103.    N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-2-[(cis-4-hydroxycyclohexyl)amino]-4-(4-methylpiperazin-1-yl)benzamide;-   104.    N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-2-[(trans-4-hydroxycyclohexyl)amino]-4-(4-methylpiperazin-1-yl)benzamide;-   105.    N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-2-[(2-hydroxyethyl)amino]-4-(4-methylpiperazin-1-yl)benzamide;-   106.    2-[(azetidin-3-ylmethyl)amino]-N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methylpiperazin-1-yl)benzamide;-   107.    N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-2-{[(1-methylazetidin-3-yl)methyl]amino}-4-(4-methylpiperazin-1-yl)benzamide;-   108.    N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-[(1-methylpiperidin-4-yl)amino]-2-[tetrahydro-2H-pyran-4-ylamino]benzamide;-   109.    4-[(azetidin-3-ylmethyl)amino]-N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-2-(tetrahydro-2H-pyran-4-ylamino)benzamide;-   110.    N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-2-[(1-methylpiperidin-4-yl)amino]benzamide;-   111.    N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-2-[(1-methylpiperidin-4-yl)amino]-4-(morpholin-4-yl)benzamide;-   112.    N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-2-methoxy-4-(4-methylpiperazin-1-yl)benzamide;-   113.    N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-5-(4-methylpiperazin-1-yl)-3-(tetrahydro-2H-pyran-4-ylamino)pyridine-2-carboxamide;-   114.    N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-6-(4-methylpiperazin-l-yl)-2-(tetrahydro-2H-pyran-4-ylamino)pyridine-3-carboxamide;-   115.    1-[4-{[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]carbamoyl}-3-(tetrahydro-2H-pyran-4-ylamino)benzyl]piperidine;-   116.    N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-{[(2-methoxyethyl)(methyl)amino]methyl}-2-(tetrahydro-2H-pyran-4-ylamino)benzamide;-   117.    N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(pyrrolidin-1-ylmethyl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide;-   118.    N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(morpholin-4-ylmethyl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide;-   119.    4-(azetidin-1-ylmethyl)-N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-2-(tetrahydro-2H-pyran-4-ylamino)benzamide;-   120.    N-[5-(3,5-Difluoro-benzyl)-1H-indazol-3-yl]-2-fluoro-5-(4-methyl-piperazin-1-ylmethyl)-benzamide;-   121.    N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-2-fluoro-5-{[(2S)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]methyl}benzamide;-   122.    N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-2-fluoro-5-(morpholin-4-ylmethyl)benzamide;-   123.    N-[5-(3,5-Difluoro-benzyl)-1H-indazol-3-yl]-2-fluoro-5-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidine-1-carbonyl)-benzamide;-   124.    N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-{[(2R)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]carbonyl}benzamide;-   125.    N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-{[(2S)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]carbonyl}benzamide;-   126. N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4    {[4-pyrrolidin-1-yl)piperidin-1-yl]carbonyl}benzamide;-   127.    N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-{[(2S)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]carbonyl}-2-(tetrahydro-2H-pyran-4-ylamino)benzamide;-   128.    N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-4{[(2R)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]carbonyl}-2-(tetrahydro-2H-pyran-4-ylamino)benzamide;-   129.    N¹-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-N⁴-[2-(dimethylamino)ethyl]-N⁴-methyl-2-(tetrahydro-2H-pyran-4-ylamino)benzene-1,4-dicarboxamide;-   130. N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4    {[4-(propan-2-yl)piperazin-1-yl]carbonyl}-2-(tetrahydro-2H-pyran-1-ylamino)benzamide;-   131.    N¹-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-N⁴-[2-(dimethylamino)ethyl]-2-(tetrahydro-2H-pyran-4-ylamino)benzene-1,4-dicarboxamide;-   132.    N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-[(4-methylpiperazin-1-yl)carbonyl]-2-(tetrahydro-2H-pyran-4-ylamino)benzamide;-   133.    N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}-2-(tetrahydro-2H-pyran-4-ylamino)benzamide;-   134. N¹-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-N⁴-(1-methyl    piperidin-4-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzene-1,4-dicarboxamide;-   135.    N-[5-(2-methyl-5-fluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;-   136.    4-(4-methylpiperazin-1-yl)-N-[5-(pyridin-3-ylmethyl)-1H-indazol-3-yl]-2-(tetrahydro-2H-pyran-4-ylamino)benzamide;-   137.    N-[5-benzyl-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;-   138. ethyl    4-{[2-{[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]carbamoyl}-5-(4-methylpiperazin-1-yl)phenyl]amino}piperidine-1-carboxylate;-   139.    N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methylpiperazin-1-yl)-2-(piperidin-4-ylamino)benzamide;-   140. ethyl    5-(3,5-difluorobenzyl)-3-({[4-(4-methylpiperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)phenyl]carbonyl}amino)-1H-indazole-1-carboxylate;-   141.    N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-2-((S)-2-methoxy-1-methyl-ethylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;-   142.    N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-[(2R)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]-2-(tetrahydro-2H-pyran-4-ylamino)benzamide;-   143. N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4    {[(2R)-1-methylpyrrolidin-2-yl]methoxy}-2-(tetrahydro-2H-pyran-4-ylamino)benzamide;-   144.    N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-{[(3R)-1-methylpyrrolidin-3-yl]oxy}-2-(tetrahydro-2H-pyran-4-ylamino)benzamide;-   145.    N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-2-fluoro-5-{[(2R)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]methyl}benzamide,    and-   146.    N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-2-fluoro-5-((R)-2-pyrrolidin-1-ylmethyl-pyrrolidine-1-carbonyl)-benzamide.

Preferred specific compound of the invention is:

-   N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.

The present invention also provides a process for the preparation of acompound of formula (I) as defined above, characterized in that theprocess comprises:

i) reducing a carbonyl compound of formula (II):

wherein Ar, R, R1, R2, and R3 are as defined above, to give a compoundof formula (I_(A)), (I_(B)) or (I_(C)):

wherein Ar, R, R1, R2, R3 and R′ are as defined above;

or

i′) reacting a compound of formula (III_(A)), (III_(B)), (III_(C)) or(III_(D)):

wherein R, R1, R2, R3, R′ and R″ are as defined above, with a compoundof formula (IV):

wherein Ar is as defined above and Y represents hydroxy, or a suitableleaving group such as halogen, to give a compound of formula (I), asdefined above;

or

i″) deprotecting a compound of formula (XXII_(A)), (XXII_(C)) or(XXII_(D)):

wherein Ar, R, R1, R2, R3, R′ and R″ are as defined above and PG is asuitable protecting group such as benzyl, p-methoxybenzyl,o,p-dimethoxybenzyl, or triphenylmethyl, to give a compound of formula(I_(A)), (I_(C)) or (I_(D)):

wherein Ar, R, R1, R2, R3, R′ and R″ are as defined above, optionallyseparating the resulting compound into the single isomers, convertingthe compound of formula (I) into a different compound of formula (I),and/or into a pharmaceutically acceptable salt if desired.

The present invention further provides a process for the preparation ofa compound of formula (I_(A)), (I_(B)) or (I_(C)) as defined above,characterized in that the compound of formula (II) as defined above, isprepared according to the following steps:

a) reacting a compound of formula (XII):

wherein R1, R2 and R3 are as defined above, with an organometalliccompound of formula RMgZ (XIII), namely a Grignard reagent, wherein R isas defined above and Z is halogen, to give a compound of formula (XI):

wherein R, R1, R2 and R3 are as defined above;

b) oxidizing the resulting compound of formula (XI), to give a compoundof formula (X):

wherein R, R1, R2 and R3 are as defined above;

c) reacting the resulting compound of formula (X) with hydrazinehydrate, to give a compound of formula (IX):

wherein R, R1, R2 and R3 are as defined above;

d) protecting the resulting compound of formula (IX), to give a compoundof formula (VIII):

wherein R, R1, R2 and R3 are as defined above, and PG₁ is a suitableprotecting group such as trifluoroacetyl group;

-   -   e) protecting the resulting compound of formula (VIII), to give        a compound of formula (VII):

wherein R, R1, R2, R3, PG and PG₁ are as defined above;

f) removing the protecting group PG₁ from the resulting compound offormula (VII), to give a compound of formula (VI):

wherein R, R1, R2, R3 and PG are as defined above;

g) reacting the resulting compound of formula (VI) with a compound offormula (IV) as defined above, to give a compound of formula (V):

wherein Ar, R, R1, R2, R3 and PG are as defined above;

h) deprotecting the resulting compound of formula (V), to give acompound of formula (II) as defined above.

The present invention further provides a process for the preparation ofa compound of formula (I_(A)) as defined above, characterized in thatthe compound of formula (III_(A)) as defined above, is preparedaccording to the following steps:

j) reducing a compound of formula (XI) as defined above, in the presenceof a suitable reagent like for example NaI and Me₃SiCl, to give acompound of formula (XIV):

wherein R, R1, R2 and R3 are as defined above;

or

k) reacting a boronic acid compound of formula (XV):

wherein R1, R2 and R3 are as defined above, with a compound of formula(XVI):

wherein R is as defined above and W represents a halogen atom, such asbromine or iodine, or a suitable leaving group like sulphonates, such asmethanesulphonate or trifluoromethanesulphonate, or phosphates in thepresence of a suitable catalyst such as a Palladium catalyst, to give acompound of formula (XIV) as defined above;

l) reacting the resulting compound of formula (XIV) with hydrazinehydrate, to give a compound of formula (III_(A)) as defined above.

The present invention further provides a process for the preparation ofa compound of formula (I_(B)) as defined above, characterized in thatthe compound of formula (III_(B)) as defined above, is preparedaccording to the following steps:

l′) reacting a compound of formula (XI) as defined above with hydrazinehydrate, to give a compound of formula (III_(B)) as defined above.

The present invention further provides a process for the preparation ofa compound of formula (I_(C)) as defined above, characterized in thatthe compound of formula (III_(C)) as defined above, is preparedaccording to the following steps:

m) reacting a compound of formula (XI) as defined above with anelectrophilic alkylating agent of formula (XVIII):

R′—W′  (XVIII)

wherein R′ is as defined above and W′ represents a halogen atom such aschlorine, bromine or iodine or a suitable leaving group likesulphonates, such as methanesulphonate or trifluoromethanesulphonate, togive a compound of formula (XVII):

wherein R, R1, R2, R3 and R′ are as defined above;

l″) reacting the resulting compound of formula (XVII) with hydrazinehydrate, to give a compound of formula (III_(C)) as defined above.

The present invention further provides a process for the preparation ofa compound of formula (I_(D)) as defined above, characterized in thatthe compound of formula (III_(D1)) wherein R″ is hydrogen, having theformula:

wherein R, R1, R2, R3 and R′ are as defined above, is prepared accordingto the following steps:

-   -   n) reacting a compound of formula (XIV) as defined above, with a        compound of formula (XVIII) as defined above;

l′″) reacting the resulting of formula (XIX_(D1)):

wherein R, R1, R2, R3 and R′ are as defined above, with hydrazinehydrate, to give a compound of formula (III_(D1)) as defined above;

or

o) reacting a compound of formula (XXI):

wherein R1, R2, R3 and R′ are as defined above, with a compound offormula (XIII) as defined above, to give a compound of formula (XX):

wherein R, R1, R2, R3 and R′ are as defined above;

p) reducing the resulting compound of formula (XX), to give a compoundof formula XIX_(D1) as defined before.

The present invention further provides a process for the preparation ofa compound of formula (I_(D)) as defined above, characterized in thatthe compound of formula (III_(D2)) wherein R″ is as defined above butnot hydrogen, having the formula:

wherein R, R1, R2, R3 and R′ are as defined above, is prepared accordingto the following steps:

q) reacting a compound of formula (XIX_(D1)) as defined above, with anelectrophilic alkylating agent of formula (XXIII):

R″—W′  (XIII)

wherein R″ and W′ are as defined above, to give a compound of formula(XIX_(D2)):

wherein R, R1, R2, R3 and R′ are as defined above and R″ is as definedabove but not hydrogen;

l^(iv)) reacting the resulting compound of formula (XIX_(D2)) withhydrazine hydrate, to give a compound of formula (III_(D2)) as definedabove.

The present invention further provides a process for the preparation ofa compound of formula (I_(A)), (I_(C)) or (I_(D)) as defined above,characterized in that a compound of formula (XXII_(A)), (XXII_(C)) or(XXII_(D)) as defined above, is prepared according to the followingsteps:

r) protecting a compound of formula (III_(A)), (III_(C)) or (III_(D)) asdefined above, to give a compound of formula (XXIV_(A)), (XXIV_(C)) or(XXIV_(D)):

wherein R, R1, R2, R3, R, R″ and PG₁ are as defined above;

s) protecting the resulting compound of formula (XXIV_(A)), (XXIV_(C))or (XXIV_(D)), to give a compound of formula (XXV_(A)), (XXV_(C)) or(XXV_(D)):

wherein R, R1, R2, R3, R, R″, PG and PG₁ are as defined above;

t) removing the protecting group PG₁ from the resulting compound offormula (XXV_(A)), (XXV_(C)) or (XXV_(D)), to give a compound of formula(XXVI_(A)), (XXVI_(C)) or (XXVI_(D)):

wherein R, R1, R2, R3, R, R″ and PG are as defined above;

u) reacting the resulting compound of formula (XXVI_(A)), (XXVI_(C)) or(XXVI_(D)) with a compound of formula (IV) as defined above, to give acompound of formula (XXII_(A)), (XXII_(C)) or (XXII_(D)) as definedabove.

It is to be noted that a compound of formula (V), as defined above canbe in any one of its isomeric forms a or b or a mixture of both:

Analogously, a compound of formula (XXII_(A)), (XXII_(C)), (XXII_(D)),(XXV_(A)), (XXV_(C)), (XXV_(D)), (XXVI_(A)), (XXVI_(C)) and (XXVI_(D))as defined above, can be in any one of theirs isomeric forms a or b.

A compound of formula (II), (V), (XXII_(A)), (XXII_(C)), and (XXII_(D)),may be converted into another compound of formula (II), (V), (XXII_(A)),(XXII_(C)), and (XXII_(D)), said conversion is carried out by one ormore of the following reactions:

1) reducing a compound of formula (II), (V, (XXII_(A)), (XXII_(C)) and(XXII_(D)) wherein Ar is a substituted aryl and one of the substituentsis NO₂, for obtaining a compound of formula (II), (V), (XXII_(A)),(XXII_(C)), and (XXII_(D)) wherein such substituent is NH₂;

2) acylating a compound of formula (II), (V), (XXII_(A)), (XXII_(C)),and (XXII_(D)), wherein Ar is a substituted aryl and one of thesubstituents is NH₂, by reaction with an acylating agent of formula(XXVII) or (XXVIII):

wherein R4 and Y are as defined above, for obtaining a compound offormula (II), (V), (XXII_(A)), (XXII_(C)), and (XXII_(D)) wherein suchsubstituent is a NHCOR4 or NHSO₂R4 residue, wherein R4 is as definedabove;

3) reacting a compound of formula (II), (V), (XXII_(A)), (XXII_(C)), and(XXII_(D)), wherein Ar is a substituted aryl and one of the substituentsis NH₂, with a suitable aldehyde or ketone in the presence of a reducingagent, for obtaining a compound of formula (II), (V), (XXII_(A)),(XXII_(C)), and (XXII_(D)), wherein such substituent is a NR5R6 group,wherein one of the R5 or R6 is hydrogen and the other is an optionallyfurther substituted straight or branched C₁-C₆ alkyl, C₃-C₆ cycloalkyl,heterocyclyl, aryl, R8R9N—C₂-C₆ alkyl, R8O—C₂-C₆ alkyl, wherein R8 andR9 are as defined above.

A compound of formula (I) may be converted into another compound offormula (I), said conversion is carried out by one or more of thefollowing reactions: 4) reducing a compound of formula (I) wherein Ar isa substituted aryl and one of the substituents is NO₂, for obtaining acompound of formula (I) wherein such substituent is NH₂;

5) acylating a compound of formula (I), wherein Ar is a substituted aryland one of the substituents is NH₂, by reaction with a compound offormula (XXVII) or (XXVIII) as defined above, followed by selectivedeprotection of the acyl group on the pyrazole ring for obtaining acompound of formula (I) wherein such substituent is a NHCOR4 or NHSO₂R4residue, wherein R4 is as defined above;

6) reacting a compound of formula (I), wherein Ar is a substituted aryland one of the substituents is NH₂, with a suitable aldehyde or ketonein the presence of a reducing agent, for obtaining a compound of formula(I), wherein such substituent is a NR5R6 group, wherein one of the R5 orR6 are defined as in conversion 3).

The synthesis of a compound of formula (I), according to the syntheticprocess described above, can be conducted in a stepwise manner, wherebyeach intermediate is isolated and purified by standard purificationtechniques, like, for example, column chromatography, before carryingout the subsequent reaction. Alternatively, two or more steps of thesynthetic sequence can be carried out in a so-called “one-pot”procedure, as known in the art, whereby only the compound resulting fromthe two or more steps is isolated and purified.

Schemes 1-4 below show the preparation of a compound of formula (I)wherein X, Ar, R, R1, R2 and R3 have the above meanings.

According to step i), a compound of formula (I_(A)), (I_(B)) or (I_(C))can be obtained by reducing a compound of formula (II) in a variety ofways and experimental conditions known in the art. Preferably thisreduction is conducted in the presence of sodium borohydride, sodiumcyanoborohydride, sodium borohydride/trifluoracetic acid,zinc/hydrochloric acid, tin chloride/acetic acid, in a suitable solvent,such as toluene, dichloromethane, chloroform, diethyl ether,tetrahydrofuran, 1,4-dioxan, methanol, ethanol, isopropanol, acetic acidat a temperature ranging from about −10° C. to reflux and for a periodof time varying from about 1 hour to about 96 hours. According to theexperimental conditions, a compound of formula (I_(A)), (I_(B)) or(I_(C)) can be isolated as major product.

According to step i′) a compound of formula (I_(A)), (I_(B)), (I_(C)) or(I_(D)) can be obtained by reacting a compound of formula (III_(A)),(III_(B)), (III_(C)) or (III_(D)) with a compound of formula (IV) in avariety of ways and experimental conditions, which are widely known inthe art for condensation reactions. Preferably a compound of formula(IV) wherein Y is hydroxy is converted into its corresponding acylchloride wherein Y is chlorine in the presence of thionyl chloride oroxalyl chloride, in a suitable solvent, such as toluene,dichloromethane, chloroform, diethyl ether, tetrahydrofuran,1,4-dioxane, at a temperature ranging from about −10° C. to reflux andfor a period of time varying from about 1 hour to about 96 hours. Theacyl chloride is isolated by evaporation of the solvent and furtherreacted with (III_(A)), (III_(B)), (III_(C)) or (III_(D)) in thepresence of a base such a pyridine, triethylamine orN-ethyldiisopropylamine in a suitable solvent, such as toluene,dichloromethane, chloroform, diethyl ether, tetrahydrofuran,1,4-dioxane, at a temperature ranging from about −40° C. to reflux andfor a period of time varying from about 1 hour to about 96 hours.Alternatively, a compound of formula (IV) is reacted with a compound offormula (III_(A)), (III_(B)), (III_(C)) or (III_(D)) in the presence ofan activating agent such as hydroxybenzotriazole, dicyclohexylcarbodiimide, diisopropyl carbodiimide,1-ethyl-3-(3′-dimethylamino)carbodiimide hydrochloric acid salt.Preferably, this reaction is carried out in a suitable solvent such as,for instance, tetrahydrofuran, dichloromethane, toluene, 1,4-dioxane,and in the presence of a proton scavenger such as, for example,pyridine, triethylamine, N,N-diisopropylethylamine, at a temperatureranging from room temperature to reflux, for a time ranging from about30 min. to about 96 hours.

According to step i″) a compound of formula (I_(A)), (I_(C)) or (I_(D))can be obtained by deprotecting a compound of formula (XXII_(A)),(XXII_(C)) or (XXII_(D)) in a variety of ways and experimentalconditions, which are widely known in the art. Preferably in the case ofan acyl residue, this reaction is be carried out under basic conditions,for instance in the presence of sodium hydroxide, potassium hydroxide,lithium hydroxide or barium hydroxide, or of a tertiary amine such astriethylamine or diisopropylethylamine, or of hydrazine, and in asuitable solvent such as methanol, ethanol, tetrahydrofuran,N,N-dimethylformamide, water and mixtures thereof. Typically, thereaction is carried out at a temperature ranging from room temperatureto reflux and for a time varying from about 30 minutes to about 96hours. In the case of PG represents a suitable protecting group such asbenzyl, p-methoxybenzyl, o,p-dimethoxybenzyl, or triphenylmethyl thetransformation can be carried out under conditions analogous to thatreported in step h).

According to step a), the transformation of a compound of formula (XII)into a compound of formula (XI) can be accomplished in a variety of waysand experimental conditions, according to conventional methods, whichare widely known in the literature by using Grignard reagents of formula(XIII). Preferably the reaction of a compound of formula (XII) withorganometallic reagents is carried out in a suitable solvent such as,for instance, tetrahydrofuran, 1,4-dioxane, and diethylether at atemperature ranging from −78° C. to room temperature and for a timevarying from about 30 minutes to about 96 hours.

According to step b), the oxidation of a compound of formula (XI) to acompound of formula (X) can be carried out in a variety of ways,according to conventional methods for oxidizing alcohols to ketones.Preferably this reaction is carried out in a suitable solvent such as,for instance, methanol, ethanol, tert-butanol, water, tetrahydrofuran,1,4-dioxane, toluene, acetic acid, trifluoroacetic acid,dichloromethane, dichloroethane, acetonitrile, dimethylsulfoxide, or amixture thereof, in the presence of a suitable oxidizing agent, such as,for instance, 3-chloroperbenzoic acid, hydrogen peroxide, Dess-Martinperiodinane, oxone, potassium permanganate, sodium periodate, periodicacid and catalytic chromium (VI) oxide, tetrapropylammonium perrutenate,ruthenium chloride. Typically, the reaction is carried out at atemperature ranging from −78° C. to reflux and for a time varying fromabout 30 minutes to about 96 hours.

According to step c), the transformation of a compound of formula (X)into a compound of formula (IX) can be accomplished in a variety of waysand experimental conditions, which are widely known in the art for thepreparation of 3-aminoindazoles. Preferably the reaction of a compoundof formula (X) with hydrazine is carried out in a suitable solvent suchas, for instance, toluene, tetrahydrofuran, 1,4-dioxane, dimethylsulfoxide, acetonitrile, methanol, ethanol or n-butanol at a temperatureranging from 0° C. to reflux and for a period of time varying from about1 hour to about 96 hours. The addition of an acid such as, preferably,hydrochloric acid or acetic acid, may be required in order to catalysethe reaction.

According to step d), a compound of formula (IX) may be transformed intoa compound of formula (VIII) in a variety of ways and experimentalconditions which are widely known in the art for protection of theprimary amino group. Preferably the reaction is carried out by treatmentwith an excess of trifluoroacetic anhydride or trifluoroacetyl chloridein a suitable solvent such as acetonitrile, tetrahydrofuran, toluene,dichloromethane. Typically, the reaction is carried out at a temperatureranging from 0° C. to about 110° C. and for a time varying from about 30minutes to about 96 hours. Work-up of the reaction mixture with a proticsolvent, such as, for instance, water, methanol, ethanol or mixturesthereof, or with a water solution of sodium hydrogencarbonate leads toselective hydrolysis of the trifluoroacetyl group on the indazole ring.In the case of the preparation of phthalimido derivative, the reactionis carried out by treatment with phthalic anhydride, under basicconditions, for instance in the presence of1,8-diazabicyclo[5.4.0]undec-7-ene, N,N-dimethylaminopyridine, pyridine,triethylamine, and in a suitable solvent such as acetonitrile,tetrahydrofuran, N,N-dimethylformamide, toluene, dichloromethane, waterand mixtures thereof. Typically, the reaction is carried out at atemperature ranging from room temperature to about 110° C. and for atime varying from about 30 minutes to about 96 hours.

According to step e), the reaction of a compound of formula (VIII) toobtain a compound of formula (VII) may be carried out in a variety ofways and experimental conditions. Preferably when PG is atriphenylmethyl group the reaction is carried out by treatment withtrityl chloride in a suitable solvent such as, for instance,tetrahydrofuran, dichloromethane, toluene, 1,4-dioxane, and in thepresence of a proton scavenger such as, preferably,1,8-diazabicyclo[5.4.0]undec-7-ene, triethylamine,N,N-diisopropylethylamine, pyridine, at a temperature ranging from roomtemperature to reflux, for a time ranging from about 30 min. to about 96hours.

According to step f) a compound of formula (VII) can be transformed intoa compound of formula (VI) by removal of a suitable protecting groupsuch as the trifluoroacetyl group, according to conventional methods.Preferably the reaction is carried out by treatment with an organic orinorganic base such as potassium carbonate, sodium hydroxide, ammonia,triethylamine, N,N-diisopropylethylamine in a suitable solvent such as,for instance, tetrahydrofuran, dichloromethane, toluene, 1,4-dioxane,methanol, ethanol, water or mixtures thereof at a temperature rangingfrom room temperature to reflux, for a time ranging from about 30 min.to about 96 hours.

According to step g) a compound of formula (VI) can be transformed intoa compound of formula (V) in a variety of ways and experimentalconditions, which are widely known in the art for condensationreactions. Preferably it is carried out in a way analogous to thatreported for step i′).

According to step h), a compound of formula (V) can be transformed intoa compound of formula (II) by deprotection of the endocyclic indazolenitrogen atom according to conventional methods enabling the selectivehydrolysis of benzyl, 4-methoxybenzyl, 2,4-dimethoxybenzyl andtriphenylmethyl protecting groups. Preferably this reaction is run underacidic conditions, preferably in the presence of an inorganic or organicacid such as hydrochloric, trifluoroacetic or methanesulfonic acid, in asuitable solvent such as dichloromethane, 1,4-dioxane, a lower alcohol,such as methanol or ethanol, at a temperature ranging from roomtemperature to about 80° C. and for a period of time varying from about1 hour to about 48 hours. In alternative, this reaction is carried outunder reducting condition, such as, for instance, in the presence ofhydrogen and a hydrogenation catalyst in a suitable solvent such asethanol, methanol, ethyl acetate, or a mixture thereof. The catalyst isusually a metal, most often a palladium derivative such as, forinstance, palladium hydroxide or palladium black.

According to step j), the reduction of a compound of formula (XI) to acompound of formula (XIV) can be carried out in a variety of ways,according to conventional methods for reducing alcohols to alkane.Preferably this reaction is carried out in a suitable solvent such as,for instance, methanol, ethanol, tetrahydrofuran, 1,4-dioxane, aceticacid, dichloromethane, acetonitrile, or a mixture thereof, in thepresence of a suitable reducing system, such as, for instance,trimethylsilyl chloride/sodium iodide, dichlorodimethylsilane/sodiumiodide, triethylsilane/trifluoroacetic anhydride,sodiumborohydride/trifluoroacetic acid. Typically, the reaction iscarried out at a temperature ranging from −10° C. to reflux and for atime varying from about 30 minutes to about 96 hours.

According to step k), the transformation of a compound of formula (XV)into a compound of formula (XIV) in the presence of a compound offormula (XVI), can be carried out in a variety of ways, according toconventional methods for boron-derivatives coupling, namely Suzuki-likereactions. Preferably, this reaction is carried out in a suitablesolvent such as, for instance, ethanol, water, tetrahydrofuran, dioxane,acetone, N,N-dimethylformamide, dimethoxyethane, toluene, xylene, or amixture thereof, in the presence of a suitable base, such as, forinstance, triethylamine, diisopropylethylamine, sodium, potassium orcesium carbonate, potassium phosphate, sodium hydroxide or cesiumfluoride, at a temperature ranging from −20° C. to reflux and for a timevarying from about 1 hour to about 96 hours. The catalyst is usually ametal, most often a palladium derivative such as, for instance,palladium chloride or palladium acetate in the presence of a suitableligand such as, for instance, triphenylphosphine.

According to step l), the transformation of a compound of formula (XIV)into a compound of formula (III_(A)) can be carried out in a variety ofways and experimental conditions. Preferably it is carried out in a wayanalogous to that reported for step c). According to step l′) thetransformation of a compound of formula (XI) into a compound of formula(III_(B)) can be carried out in a variety of ways and experimentalconditions. Preferably it is carried out in a way analogous to thatreported for step c). According to step m), the transformation of acompound of formula (XI) into a compound of formula (XVII) in thepresence of a compound of formula (XVIII) can be carried out in avariety of ways, according to conventional methods for O-alkylationreactions. Preferably, this reaction is carried out in a suitablesolvent such as, for instance, tetrahydrofuran, dioxane,N,N-dimethylformamide, dimethoxyethane, in the presence of a suitablebase, such as, for instance, triethylamine, diisopropylethylamine,sodium, potassium or cesium carbonate, sodium hydride, at a temperatureranging from −78° C. to reflux and for a time varying from about 1 hourto about 96 hours. Alkylating agent is usually a halogen or asulphonates derivative; most often the leaving group is iodo, bromo,triflate or mesylate.

According to step l″) the transformation of a compound of formula (XVII)into a compound of formula (III_(C)) can be carried out in a variety ofways and experimental conditions. Preferably it is carried out in a wayanalogous to that reported for step c).

According to step n), the transformation of a compound of formula (XIV)into a compound of formula (XIX_(D1)) in the presence of a compound offormula (XVIII) can be carried out in a variety of ways, according toconventional methods for C-alkylation reactions. Preferably it iscarried out in a way analogous to that reported for step m).

According to step l′″) the transformation of a compound of formula(XIX_(D1)) into a compound of formula (III_(D1)) can be carried out in avariety of ways and experimental conditions. Preferably it is carriedout in a way analogous to that reported for step c).

According to step o), the transformation of a compound of formula (XXI)into a compound of formula (XX) in the presence of a compound of formula(XIII) can be carried out in a variety of ways and experimentalconditions. Preferably it is carried out in a way analogous to thatreported for step a).

According to step p), the transformation of a compound of formula (XX)into a compound of formula (XIX_(D1)) can be carried out in a variety ofways and experimental conditions. Preferably it is carried out in a wayanalogous to that reported for step j).

According to step q) the transformation of a compound of formula(XIX_(D1)) into a compound of formula (XIX_(D2)) in the presence of acompound of formula (XXIII) can be carried out in a variety of ways andexperimental conditions. Preferably it is carried out in a way analogousto that reported for step m).

According to Step l^(Iv)), the transformation of a compound of formula(XIX_(D2)) into a compound of formula (III_(D2)) can be carried out in avariety of ways and experimental conditions. Preferably it is carriedout in a way analogous to that reported for step c).

According to step r), a compound of formula (III_(A)), (III_(C)) or(III_(D)) may be transformed into a compound of formula (XXIV_(A)),(XXIV_(C)) or (XXIV_(D)) in a variety of ways and experimentalconditions which are widely known in the art for protection of theprimary amino group. Preferably it is carried out in a way analogous tothat reported for step d).

According to step s), the reaction of a compound of formula (XXIV_(A)),(XXIV_(C)) or (XXIV_(D)) to obtain a compound of formula (XXV_(A)),(XXV_(C)) or (XXV_(D)) may be carried out in a variety of ways andexperimental conditions. Preferably it is carried out in a way analogousto that reported for step e).

According to step t) a compound of formula (XXV_(A)), (XXV_(C)) or(XXV_(D)) can be transformed into a compound of formula (XXVI_(A)),(XXVI_(C)) or (XXVI_(D)) by removal of a suitable protecting group suchas the trifluoroacetyl group, according to conventional methods.Preferably it is carried out in a way analogous to that reported forstep f).

According to step u) a compound of formula (XXVI_(A)), (XXVI_(C)) or(XXVI_(D)) can be transformed into a compound of formula (XXII_(A)),(XXII_(C)) or (XXII_(D)) in a variety of ways and experimentalconditions, which are widely known in the art for condensationreactions. Preferably it is carried out in a way analogous to thatreported for step i′).

According to the conversion described under 1) the reduction of acompound of formula (II), (V), (XXII_(A)), (XXII_(C)) or (XXII_(D)),wherein Ar is a substituted aryl and one of the substituents is nitro,to a compound of formula (II), (V), (XXII_(A)), (XXII_(C)) or(XXII_(D)), wherein such substituent is amino, can be carried out in avariety of ways, according to conventional methods well known in theliterature. Preferably this conversion is carried out in a suitablesolvent such as, for instance, methanol, ethanol, water,tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, acetic acid, or amixture thereof, in the presence of a suitable reducing agent, such as,for instance, hydrogen and a hydrogenation catalyst, or by treatmentwith cyclohexene or cyclohexadiene, or formic acid or ammonium formateand a hydrogenation catalyst, or a metal such as iron or zinc in thepresence of an inorganic acid, such as hydrochloric acid, or bytreatment with tin (II) chloride, at a temperature ranging from 0° C. toreflux and for a time varying from about 1 hour to about 96 hours. Thehydrogenation catalyst is usually a metal, most often palladium, whichcan be used as such or supported on carbon.

According to the conversion described under 2) the acylation of acompound of formula (II), (V), (XXII_(A)), (XXII_(C)) or (XXII_(D)),wherein Ar is a substituted aryl and one of the substituents is amino,by reaction with an acetylating agent of formula (XXVII) or (XXVIII) togive a compound of formula (II), (V), (XXII_(A)), (XXII_(C)) or(XXII_(D)), wherein such substituent is a NHCOR4 or NHSO₂R4 residue, canbe carried out in a variety of ways, according to conventional methodswell known in the literature. Preferably this conversion is carried outunder conditions analogous to that reported for step i′).

According to the conversion described under 3) the reductive aminationof a compound of formula (II), (V), (XXII_(A)), (XXII_(C)) or(XXII_(D)), wherein Ar is a substituted aryl and one of the substituentsis amino, by reaction with a suitable aldehyde or ketone can beconducted in a variety of ways, according to conventional methods forcarrying out reductive alkylations. Preferably, this reaction is carriedout in a suitable solvent such as, for instance, methanol,N,N-dimethylformamide, dichloromethane, tetrahydrofuran, or a mixturethereof, in the presence of a suitable reducing agent such as, forinstance, sodium borohydride, tetra-alkylammonium borohydride, sodiumcyano borohydride, sodium triacetoxyborohydride, tetramethylammoniumtriacetoxy borohydride and in presence of an acid catalyst, such as, forinstance, acetic acid or trifluoroacetic acid, at a temperature rangingfrom about 0° C. to reflux and for a time varying from about 1 hour toabout 96 hours.

According to the conversion described under 4) the reduction of acompound of formula (I), wherein Ar is a substituted aryl and one of thesubstituents is nitro, to a compound of formula (I) wherein suchsubstituent is amino, can be carried out in a variety of ways, accordingto conventional methods well known in the literature. Preferably thisconversion is carried out under conditions analogous to that reportedfor conversion 1).

According to the conversion described under 5) the acylation of acompound of formula (I) wherein Ar is a substituted aryl and one of thesubstituents is amino, by reaction with an acetylating agent of formula(XXVII) or (XXVIII) to give a compound of formula (I) wherein suchsubstituent is a NHCOR4 or NHSO₂R4 residue, can be carried out in avariety of ways, according to conventional methods well known in theliterature. Preferably this conversion is carried out under conditionsanalogous to that reported for conversion 2).

According to the conversion described under 6) the reductive amminationof a compound of formula (I) wherein Ar is a substituted aryl and one ofthe substituents is amino, by reaction with a suitable aldehyde orketone can be conducted in a variety of ways, according to conventionalmethods for carrying out reductive alkylations. Preferably, thisreaction is carried out under conditions analogous to that reported forconversion 3).

It is known to the skilled person that when a compound of formula (IV)or formula (XXVII) carries functional groups that may interfere inacylation reactions, such groups have to be protected before carryingout the reaction. In particular, when a compound of formula (IV) orformula (XXVII) is substituted by residues of general formula NR5R6,OR7, SR7, R8R9N—C₁-C₆ alkyl, or R8O—C₁-C₆ alkyl wherein R7 or at leastone of R5 and R6 or at least one of R8 and R9 represent hydrogen, suchgroups may be protected as known in the art. It is also known to theskilled person that such protecting group may be removed just after thereaction or at a later stage in the synthetic process.

The deprotection of a compound of formula (I), (XXII_(A)), (XXII_(C) or(XII_(D)) wherein Ar is a substituted aryl and one of the substituentsis a protected amino group can be made in a variety of ways according toconventional methods for deprotecting amino groups. Depending on theamino protecting group, this reaction can be conducted in differentways. In one aspect, such reaction can be carried out by treatment withan inorganic acid, such as hydrochloric, sulphuric or perchloric acid,or an organic acid, such as trifluoroacetic or methanesulfonic acid, ina suitable solvent, such as water, methanol, ethanol, 1,4-dioxane,tetrahydrofuran, diethyl ether, diisopropyl ether, acetonitrile,N,N-dimethylformamide, dichloromethane or mixtures thereof, at atemperature ranging from −10° C. to 80° C., and for a period of timeranging from 30 minutes to 48 hours. In another aspect, such reactioncan be carried out by treatment with an inorganic base, such as lithiumor sodium or potassium hydroxide, or sodium or potassium or caesiumcarbonate, or with an organic base, such as triethylamine orN,N-diisopropylethylamine, or with anhydrous hydrazine or hydrazinehydrate in a suitable solvent such as water, methanol, ethanol,1,4-dioxane, tetrahydrofuran, diethyl ether, diisopropyl ether,acetonitrile, N,N-dimethylformamide, dichlorometane or mixtures thereofat a temperature ranging from −10° C. to 80° C., and for a period oftime ranging from 30 minutes to 72 hours.

Substituted indazole derivatives can be prepared using standardprocedures in organic synthesis as reported, for instance, in Smith,Michael—March's Advanced Organic Chemistry: reactions mechanisms andstructure—5^(th) Edition, Michael B. Smith and Jerry March, John Wiley &Sons Inc., New York (N.Y.), 2001. It is known to the skilled person thattransformation of a chemical function into another may require that oneor more reactive centers in the compound containing this function beprotected in order to avoid undesired side reactions. Protection of suchreactive centers, and subsequent deprotection at the end of thesynthetic transformations, can be accomplished following standardprocedures described, for instance, in: Green, Theodora W. and Wuts,Peter G. M. —Protective Groups in Organic Synthesis, Third Edition, JohnWiley & Sons Inc., New York (N.Y.), 1999.

In cases where a compound of formula (I) contains one or more asymmetriccenters, said compound can be separated into the single isomers byprocedures known to those skilled in the art. Such procedures comprisestandard chromatographic techniques, including chromatography using achiral stationary phase, or crystallization. General methods forseparation of compounds containing one or more asymmetric centers arereported, for instance, in Jacques, Jean; Collet, André; Wilen, SamuelH.,—Enantiomers, Racemates, and Resolutions, John Wiley & Sons Inc., NewYork (N.Y.), 1981.

A compound of formula (I) can also be transformed into apharmaceutically acceptable salt according to standard procedures thatare known to those skilled in the art. Alternatively, a compound offormula (I) that is obtained as a salt can be transformed into the freebase or the free acid according to standard procedures that are known tothe skilled person.

The starting materials of the process of the present invention, i.e.compounds of formula (XII), (XIII), (XV), (XVI), (XVIII), (XXIII), and(XXI) are either commercially available or can be prepared by usingwell-known methods.

For example, the compounds of formula (XIII) can be easily obtainedaccording to conventional procedures, which are widely known in the artfor Grignard reagents formation, as reported in the following scheme:

RZ+Mg→RMgZ  (XIII)

For example, the compounds of formula (XV) can be easily prepared fromthe corresponding halogen derivatives, as reported in the followingscheme (see for example WANG, X.-J. et al.; Org Lett 2006, 8 (2),305-307):

For example, the compounds of formula (XVI) can be easily obtained byelaboration of the corresponding alcohols derivatives by workingaccording to conventional synthetic methods.

For example, the compounds of formula (XXI) can be easily obtained byoxidation of the corresponding alcohols derivatives by working accordingto conventional synthetic methods.

Another object of the present invention is to provide an intermediate offormula (III_(A′)), (III_(B′)), (III_(C′)), or (III_(D′)):

wherein R is an optionally substituted C₃-C₆ cycloalkyl, aryl orheteroaryl, and

R1, R2, R3, R′ and R″ are as defined above, with the proviso that thefollowing compounds are excluded:

-   6-(3-amino-1H-indazol-5-ylmethyl)-3-isopropyl-1-(2,4,6-trichloro-phenyl)-1,7-dihydro-pyrazolo[3,4-d]pyrimidin-4-one    and-   1-[(3-amino-1H-indazol-5-yl)methyl]-3-({1-[2-(dimethylamino)ethyl]-1H-benzimidazol-2-yl}methyl)-1,3-dihydro-2H-benzimidazol-2-one.

Another object of the present invention is to provide an intermediate offormula of the formula (XII_(A)), (XXII_(C)) or (XXII_(D)):

wherein Ar, R, R1, R2, R3, R′, R″ and PG are as defined above.

Another object of the present invention is to provide a compound offormula (XXVII):

wherein Ar, R, R1, R2 and R3 are as defined above and PG₂ isethoxycarbonyl or 2-methoxyethylcarbonyl.

The present invention further provides a process for the preparation ofa compound of formula (XXVII) as defined above, characterized in thatthe process comprises:

v) protecting a compound of formula (I) as defined above, to give acompound of formula (XXVII)

wherein R, R1, R2, R3 and PG₂ are as defined above.

According to step v), the protection of a compound of formula (I) into acompound of formula (XXVII) can be accomplished in a variety of ways andexperimental conditions. Preferably the reaction is carried out bytreatment with a base such as lithium diisopropylamide, sodium hydrideor lithium, sodium or potassium bis(trimethylsilyl)amide in a suitablesolvent such as, for instance, toluene, tetrahydrofurane, 1,4-dioxane,diethylether, N,N-dimethylformamide, dimethoxyethane at a temperatureranging from −78° C. to room temperature and for a period of timevarying from about 10 minutes to about 96 hours. The electrophile isusually a chloroformate derivative such as, for instance, ethylchloroformate or 2-methoxyethyl chloroformate.

Pharmacology

The short forms and abbreviations used herein have the followingmeaning:

Ci Curie

DMSO dimethylsulfoxide

ID identity

KDa kiloDalton

microCi microCurie

mg milligram

microg microgram

mL milliliter

microL microliter

M molar

mM millimolar

microM micromolar

nM nanomolar

Assays

Compounds of the present invention were tested in biochemical assays, asdescribed below.

Preparation of ALK Cytoplasmic Domain for Use in Biochemical AssayCloning and Expression

ALK cytoplasmic domain, corresponding to the residue 1060-1620 (thenumbers of the amino acid residues refer to the Genbank accession numberNP 004295.2) was PCR amplified from a human testis cDNA library.

Amplification was performed using the forward oligonucleotide:

(SEQ ID NO: 1) 5′GGGGACAAGTTTGTTACAAAAAAGCAGGCTTACTGGAAGTTCTGTTCCAGGGGCCCCGCCGGAAGCACCAGGAGCTG-3′and the reverse oligonucleotide:

(SEQ ID NO: 2) 5′GGGGACCACTTTGTACAAGAAAGCTGGGTTTCAGGGCCCAGGCTGGTTCATGCTATT-3′.

For cloning purposes, the oligonucleotides included attB sites in orderto obtain an attB-flanked PCR product suitable for cloning using theGateway technology (Invitrogen). Furthermore, for purification purposes,forward primer included a PreScission cleavage site (AmershamBiosciences). The resulting PCR product was cloned in the baculovirusexpression vector pVL1393 (Invitrogen) Gateway-modified. For expressionand purification purpose, a GST tag was added N-terminal to the ALKcytoplasmic domain. Cloning was performed according to the protocolsdescribed in the Gateway manual (Invitrogen).

Baculovirus was generated by cotransfecting Sf9 insect cells withexpression vector and the viral DNA using the BaculoGold™ tranfectionkit (Pharmingen). Viral supernatant was recovered after 5 days andsubjected to 3 rounds of amplification to increase viral titer.

Recombinant protein was produced by infecting Sf21 insect cells at thedensity of 1×10⁶ cells/mL with 30 mL viral supernatant per billion cellswith shaking at 27° C. After 48 hours of infections the cells wererecovered, pelletted and freezed at −80° C.

Protein Purification

Cells were resuspended in lysis buffer (Tris-HCl 50 mM pH8, NaCl 150 mM,CHAPS 0.2%, DTT 20 mM, glycerol 20%, “Complete” protease inhibitorcocktail (Roche Diagnostics), Na₃VO₄ 1 mM and lysed by liquid extrusionwith a Gaulin homogenizer (Niro Soavi Italy). The lysate was cleared bycentrifugation at 20000 g for 30 minutes and loaded on a GlutathioneSepharose 4B (Amersham Biosciences) column.

After extensive wash, recombinant protein was eluted with 10 mMGlutathione in 100 mM Tris-HCl pH8, 10% glycerol.

Affinity purified GST-ALK was loaded on a Heparin Sepharose™ FF(Amersham Biosciences) column and eluted with 50 mM NaCl, 25 mM TRIS pH7.5, 2 mM DTT, 20% glycerol.

The eluted fractions were pooled and dialyzed against 150 mM NaCl, 50 mMTris-HCl pH 7.4, 2 mM DTT, 20% glycerol.

Purified protein was stored at −80° C. prior its use in biochemicalassay.

Biochemical Assay for Inhibitors of ALK Kinase Activity

ALK enzyme needs pre-activation in order to linearize reaction kinetics.

i. Kinase Buffer (KB) for ALK

Kinase buffer was composed of 50 mM HEPES pH 7.5 containing 1 mM MnCl₂,mM MgCl₂, 1 mM DTT, 3 microM Na₃VO₄, and 0.2 mg/mL BSA. 3×KB is bufferof the same composition and pH as KB, but with three times theconcentration of each component.

ii. Assay Conditions

The kinase assay was run with a final enzyme concentration of 20 nM, inthe presence of 8 microM ATP, 1 nM ³³P-γ-ATP and 2 microM MBP. The MPBwas purchased from Sigma-Aldrich, St. Louis, Mo., USA.

Cell-Based Assays for Inhibitors of ALK Kinase Activity

Western Blot Analysis of ALK and STAT3 phosohorylation in Karpas-299,SR-786 and SUP-M2 Anaplastic Large Cell Lymphoma Cell Lines

Karpas-299, SR-786 and SUP-M2 cells (DSMZ, Braunschwiegh, Germany) wereseeded in 6-well tissue culture plates at 5×10⁵ cells/mL in RPMI-1640medium+2 mM glutamine+10% to 15% FCS (EuroClone, Italy), and incubatedovernight at 37° C., 5% CO₂, 100% relative humidity. After thisincubation, cells were treated with desired concentrations of compoundfor 2 hours at 37° C. Cells were collected by centrifugation at 248×gfor 5 minutes, washed with cold PBS, centrifuged again at 248×g for 5minutes and then lysed in 100 mM Tris-HCl pH 7.4, 2% SDS, 1 mM Na₃VO₄,protease inhibitor cocktail [Sigma-Aldrich product #P8340], phosphataseinhibitor cocktail [Sigma-Aldrich products #P2850+#P5726]). After briefsonication, cell lysates were cleared by centrifugation at 10,000×g for20 minutes at room temperature and 20 microg/lane of cleared lysateprotein were run on NuPAGE gels (NuPAGE 4-12% 10-lane Bis-Tris gels,Invitrogen) with MOPS running buffer, then transferred onto Hybond-ECLnitrocellulose filters (Amersham Biosciences, Little Chalfont,Buckinghamshire, UK) using Mini PROTEAN II chambers (Bio-RadLaboratories, Hercules, Calif., USA). Filters bearing transferredprotein were incubated for 1 hour in blocking buffer (TBS+5% Non-fat DryMilk [#1706404 Bio-rad, Hercules, Calif., USA]+0.1% Tween 20), andprobed over-night in TBS+5% BSA+0.1% Tween 20 at 4° C. containing 1/500anti-phosho-ALK Tyr 1604 antibody (product #3341 Cell SignalingTechnology, Beverly, Mass., USA) for dectection of phosphorylated ALK or1/500 mouse anti-ALK antibody (product #35-4300, Zymed Laboratories,South San Francisco, Calif., USA) for the detection of total ALK or1/500 mouse anti-phospho STAT3 Tyr 705 antibody (product #612357, BDTransduction Laboratories, Canada) for dectection of phosphorylatedSTAT3 or 1/1000 mouse anti-STAT3 antibody (product #610190 BDTransduction Laboratories, Canada) for detection of total STAT3.

In all cases, filters were then washed for 20 minutes with severalchanges of TBS+0.1% Tween 20, and incubated for 1 hour in TBS+5% Non-fatDry Milk+0.1% Tween 20 containing 1/10000 dilution of horseradishperoxidase conjugated anti-rabbit or mouse IgG (Amersham, product#NA934), then were washed again and developed using the ECLchemiluminescence system (Amersham) according to manufacturer'srecommendations. Unless otherwise stated, reagents used were fromSigma-Aldrich, St. Louis, Mo., USA.

In Vitro Cell Proliferation Assay for Inhibitors of ALK Kinase Activity

The human ALCL cell lines Karpas-299, SR-786 and SUP-M2 were seeded in96 well plate (PerkinElmer, Wellesley, Mass., USA) 1×10⁵ cells/mL inRPMI-1640 medium+2 mM glutamine+10% to 15% FCS (EuroClone, Italy), (100microL/well) and maintained at 37° C., 5% CO₂, 100% relative humidity.The following day, plates were treated in duplicates with an appropriatedilution of compounds starting from a 10 mM stock solution in DMSO(final DMSO concentration: 0.1%). Eight untreated control wells wereincluded in each plate. After 72 hours of treatment, 50 microL ofCellTiter-Glo Assay (Promega, Madison, Wis., USA) were added to eachwell and after agitation the luminescence signal is measured usingEnvision Detector (PerkinElmer Wellesley, Mass., USA).

IC₅₀ values were calculated by LSW/Data Analysis using Microsoft Excelsigmoidal curve fitting.

Preparation of IGF-1R for Use in Biochemical Assay Cloning andExpression

Human cDNA was used as template for amplification by polymerase chainreaction (PCR) of the predicted cytoplasmic portion of IGF-1R (aminoacid residues 960-1367 of precursor protein; see NCBI Entrez ProteinAccession #P08069) which includes the entire kinase domain. PCR wasconducted using the forward primer sequence5′-CTCGGATCCAGAAAGAGAAATAACAGCAGGCTG-3′ (SEQ ID NO:3) and the reverseprimer sequence 5′-CTCGGATCCTCAGCAGGTCGAAGACTGGGGCAGCGG-3′ (SEQ IDNO:4). In order to facilitate subsequent cloning steps, both primerscomprise a BamHI restriction endonuclease site sequence. This PCRproduct was cloned in frame using BamHI sticky ends into a transfervector for the baculovirus expression system, pVL1392 (Pharmingen),previously modified by insertion into the pVL 1392 multiple cloning siteof sequences encoding Glutathione S-transferase (GST) fusion protein,PreScission protease cleavage site and partial MCS cassette derived fromthe pGex-6P plasmid (Amersham BioSciences). Insertion of the IGF-1R PCRproduct described above into the pGex-6P derived BamHI site of themodified pVL1392 vector results in an open reading frame correspondingto the pGEX-6P GST protein and PreScission peptide fused with the humanIGF-1R cytoplasmic domain. In order to obtain fusion protein, Sf21insect cells (Invitrogen) are cotransfected with 2 microg of purifiedplasmid and 1 microg of virus DNA (BaculoGold™ Transfection Kit,Pharmingen), as described in the Baculovirus Instruction manual(Pharmingen). A first amplification of the virus is performed using 600microL of cotransfected virus on 6×10⁶ Sf21 in a monolayer culture, in12 mL of medium (TNM-FH Grace's medium—Pharmingen). After 3 days themedium is collected, centrifuged and transferred to a sterile tube. Asecond amplification is prepared with the same method using 2 mL on3×10⁷ cells, diluted in 40 mL of medium. For the third amplification ofvirus, 1 mL of supernatant from the second round are used per 3×10⁷cells diluted in 40 mL of medium.

Protein expression is performed in H5 insect cells infected with 14 mLvirus/1×10⁹ insect cells (MOI=1.5) for 65 h with shaking at 27° C. Cellsare harvested by centrifugation at 1200×g for 10 minutes.

Protein Purification

Cells were resuspended in phosphate buffered saline solution (PBS), 20mM dithiothreitol (DTT), 0.2% CHAPS, 20% glycerol, 1 mM OVA, “Complete”protease inhibitor cocktail (1 tablet/50 mL buffer; Roche Diagnostics,Milan, Italy) and lysed by liquid extrusion with a Gaulin homogenizer(Niro Soavi, Italy). The lysate was centrifuged at 14000×g for 45minutes and the supernatant was loaded onto a column containing 10 mLGlutathione Sepharose (Amersham Biosciences). The column was firstwashed with PBS buffer for 5 column volumes, then with 100 mM Tris pH8.0, 20% glycerol for 5 column volumes, and lastly eluted with 10 mMglutathione in 100 mM Tris pH 8.0, 20% glycerol. Fractions of 10 mL werecollected, and protein-rich fractions were pooled. Typically, 20 mg offusion protein were recovered from 1×10⁹ cells, and this wastypically >85% pure as judged by SDS-PAGE followed by Coomassiestaining.

Purified protein was stored at −80° C. prior to its use in biochemicalassays.

Biochemical Assay for Inhibitors of IGF-1R Kinase Activity

The inhibitory activity of putative kinase inhibitors and the potency ofselected compounds were determined using a trans-phosphorylation assay.

A specific substrate was incubated with the kinase in appropriate bufferconditions in the presence of ATP traced with ³³P-γ-ATP (gammaphosphate-labeled, Redivue™ Code Number AH9968, 1000-3000 Ci/mmole,Amersham Biosciences Piscataway, N.J., USA), optimal cofactors and testcompound.

At the end of the phosphorylation reaction, more than 98% cold andradioactive ATP were captured by an excess of Dowex ion exchange resin.The resin was allowed to settle to the bottom of reaction wells bygravity. Supernatant, containing substrate peptide, was subsequentlywithdrawn and transferred into a counting plate, and radioactivity(corresponding to phosphate incorporated into peptide) was evaluated byβ-counting.

Reagents/Assay Conditions

i. Dowex Resin Preparation

500 g of wet resin (SIGMA, custom prepared DOWEX resin 1×8 200-400 mesh,2.5 Kg) were weighed out and diluted to 2 L in 150 mM sodium formate, pH3.00.

The resin was allowed to settle for several hours and then thesupernatant was discarded. This washing procedure was repeated threetimes over two days. Finally, the resin was allowed to settle,supernatant was discarded and two volumes (with respect to the resinvolume) of 150 mM sodium formate buffer were added. The final pH wascirca 3.0. The washed resin was kept at 4° C. before use, and was stablefor more than one week.

ii. Kinase Buffer (KB)

Kinase buffer was composed of 50 mM HEPES pH 7.9 containing 3 mM MnCl₂,1 mM DTT, 3 microM Na₃VO₄, and 0.2 mg/mL BSA. 3×KB is buffer of the samecomposition and pH as KB, but with three times the concentration of eachcomponent.

iii. Enzyme pre-activation and preparation of 3× Enzyme Mix.

Prior to starting the kinase inhibition assay, IGF-1R waspre-phosphorylated in order to linearize reaction kinetics. To achievethis, the desired total quantity of enzyme was prepared at an enzymeconcentration of 360 nM in KB containing 100 microM ATP, and thispreparation was incubated for 30 min at 28° C. 3× Enzyme Mix wasobtained by diluting this preactivated enzyme 20-fold in 3×KB.

iv. Assay Conditions

The kinase assay was run with a final enzyme concentration of 6 nM, inthe presence of 6 microM ATP, 1 nM ³³P-γ-ATP and 10 microM substrate, acarboxy-terminally biotinylated peptide of the following sequence:KKKSPGEYVNIEFGGGGGK-biotin (SEQ ID NO:5). The peptide was obtained inbatches of >95% peptide purity from American Peptide Company, Inc.(Sunnyvale, Calif., USA).

Robotized Dowex Assay

Test reactions were performed in a total final volume of 21 microLconsisting of:

a) 7 microL/well of 3× Enzyme Mix (18 nM preactivated enzyme in 3×kinase buffer),

b) 7 microL/well of 3× substrate/ATP mix (30 microM substrate, 18 microMATP, 3 nM ³³P-γ-ATP in double-distilled water (ddH₂O),

c) 7 microL/well 3× test compounds diluted into ddH₂O-3% DMSO.

Compound Dilution and Assay Scheme is Reported Below.

i. Dilution of Compounds

10 mM stock solutions of test compounds in 100% DMSO were distributedinto 96 well 12×8 format microtiter plates.

For % inhibition studies, dilution plates at 1 mM, 100 microM and 10microM were prepared in 100% DMSO, then diluted to 3× final desiredconcentration (30, 3 and 0.3 microM) in ddH₂O, 3% DMSO. A Multimek 96(Beckman Coulter, Inc. 4300 N. Harbor Boulevard, P.O. Box 3100Fullerton, Calif. 92834-3100 USA) was used for compound pipetting intotest plates.

For IC50 determination, starting solutions of 30 microM compound in 3%DMSO were derived from 1 mM/100% DMSO stock solutions. These 30 microMstarting solutions were used for generation of a further 9 serial 1/3dilutions in ddH₂0, 3% DMSO, so as to generate a 10-point dilution curveat 3× the final assay concentration. Serial dilution was conducted in96-well plates using a Biomek 2000 (Beckman Coulter) system. Dilutioncurves of 7 compounds/plate were prepared, and each plate also includeda 10-point dilution curve of Staurosporine, as well as several negativeand positive control wells.

ii. Assay Scheme

7 microL of each test compound dilution (or control) in ddH₂O, 3% DMSOwere pipetted into each well of a 384-well, V-bottom assay plate, whichwas then transferred to a PlateTrak 12 robotized station (Perkin Elmer,45 William Street Wellesley, Mass. 02481-4078, USA) equipped with one384-tip pipetting head for starting the assay, plus one 96-tip head fordispensing the resin) prepared with reservoirs containing sufficient 3×Enzyme mix and 3×ATP mix (3×) to complete the assay run.

At the start of the assay the liquid handling system aspirates 7 microLof ATP mix, introduces an air gap inside the tips (5 microL) and thenaspirates 7 microL of 3× Enzyme Mix. To start the reaction, tipscontents were dispensed into the test wells already containing 7 microLtest compound (at 3× desired final concentration), followed by 3 cyclesof mixing, so as to restore desired final concentration for all reactioncomponents.

Plates were incubated for 60 minutes at room temperature, and then thereaction was stopped by pipetting 70 microL of Dowex resin suspensioninto the reaction mix, followed by three cycles of mixing. Afterstopping the reaction, plates were allowed to rest for one hour in orderto maximize ATP capture. At this point, 20 microL of supernatant weretransferred from each well into wells of 384-Optiplates (Perkin Elmer)containing 70 microL/well of Microscint 40 (Perkin Elmer); after 5 minof orbital shaking the plates were read on a Perkin-Elmer Top Countradioactivity counter.

iii. Data Analysis

Data were analysed using a customized version of the “Assay Explorer”software package (Elsevier MDL, San Leandro, Calif. 94577). For singlecompound concentrations, inhibitory activity was typically expressed as% inhibition obtained in presence of compound, compared to totalactivity of enzyme obtained when inhibitor is omitted.

Compounds showing desired inhibition were further analysed in order tostudy the potency of the inhibitor through IC₅₀ calculation. In thiscase, inhibition data obtained using serial dilutions of the inhibitorwere fitted by non-linear regression using the following equation:

$v = {v_{0} + \frac{\left( {v_{0} - v_{b}} \right)}{1 + 10^{n{({{\log \; {IC}_{50}} - {\log {\lbrack I\rbrack}}})}}}}$

where ν_(b) is the baseline velocity, ν is the observed reactionvelocity, ν_(o) is the velocity in the absence of inhibitors, and [I] isthe inhibitor concentration.

Cell-Based Assays for Inhibitors of IGF-1R Kinase Activity

Western Blot Analysis of Receptor Phosphorylation Following Stimulationwith IGF-1 in MCF-7 Human Breast Cancer Cells

MCF-7 cells (ATCC# HTB-22) were seeded in 12-well tissue culture platesat 2×10⁵ cells/well in E-MEM medium (MEM+Earle's BSS+2 mM glutamine+0.1mM non-essential amino acids)+10% FCS, and incubated overnight at 37°C., 5% CO2, 100% relative humidity. Cells were then starved by replacingE-MEM+10% FCS with E-MEM+0.1% BSA, and incubating overnight. After thisincubation, wells were treated with desired concentrations of compoundfor 1 hour at 37° C., and were then stimulated with 10 nM recombinanthuman IGF-1 (Invitrogen, Carlsbad, Calif., USA) for 10 minutes at 37° C.Cells were then washed with PBS and lysed in 100 microL/well cell lysisbuffer (M-PER Mammalian Protein Extraction Reagent [Product #78501,Pierce, Rockford, Ill., USA]+10 mM EDTA+Protease inhibitor cocktail[Sigma-Aldrich product #P8340]+phosphatase inhibitor cocktail[Sigma-Aldrich products #P2850+#P5726]). Cell lysates were cleared bycentrifugation at 10,000×g for 5 minutes, and 10 microg/lane of clearedlysate protein were run on NuPAGE gels (NuPAGE 4-12% 10-lane Bis-Trisgels, Invitrogen) with MOPS running buffer, then transferred ontoHybond-ECL nitrocellulose filters (Amersham Biosciences, LittleChalfont, Buckinghamshire, UK) using Mini PROTEAN II chambers (Bio-RadLaboratories, Hercules, Calif., USA). Filters bearing transferredprotein were incubated for 1 hour in blocking buffer (TBS+5% BSA+0.15%Tween 20), and probed for 2 hours in the same buffer containing 1/1000rabbit anti-phospho IGF-1R Tyr11131/InsR Tyr 1146 antibody (product#3021, Cell Signaling Technology, Beverly, Mass., USA) for the detectionof phosphorylated IGF-1R, or 1/1000 dilution of rabbit IGF-Irβ(H-60)antibody (product #sc-9038, Santa Cruz Biotechnology, Inc., Santa Cruz,Calif., USA) for detecting total IGF-1R β chain. In either case, filterswere then washed for 30 minutes with several changes of TBS+0.15% Tween20, and incubated for 1 hour in washing buffer containing 1/5000dilution of horseradish peroxidase conjugated anti-rabbit IgG (Amersham,product #NA934), then were washed again and developed using the ECLchemiluminescence system (Amersham) according to manufacturer'srecommendations. Unless otherwise stated, reagents used were fromSigma-Aldrich, St. Louis, Mo., USA.

Growth Factor Induced S6 Ribosomal Protein Phosphorylation in PrimaryHuman Fibroblasts

Phosphorylation of S6 ribosomal protein in response to growth factorstimulation of normal human dermal fibroblasts (NHDF) was used to assesscompound potency in inhibiting IGF-1 induced signal transduction incells, and selectivity towards EGF and PDGF stimulus. NHDF cellsobtained from PromoCell (Heidelberg, Germany), were maintained at 37° C.in a humidified atmosphere with 5% CO₂ in complete Fibroblast GrowthMedium (PromoCell). For assay, NHDF were seeded in 384-well tissueculture plates (clear- and flat-bottomed black plates; MatrixTechnologies Inc., Hudson, N.H., USA) at a density of 5000 cells/well inserum-free medium containing 0.1% bovine serum albumin (BSA) andincubated for 5 days. Starved cells were treated for 1 hour with desireddoses of compounds and then stimulated for a further 2 hours with either10 nM IGF-1 (Invitrogen Corp., CA, USA), 10 nM EGF (Gibco BRL, USA) or 1nM PDGF-B/B (Roche Diagnostics GmbH, Germany). Cells were then fixed inPBS/3.7% paraformaldehyde for 20 minutes at room temperature, washed ×2with PBS, and permeabilized with PBS/0.3% Triton X-100 for 15 minutes.Wells were then saturated with PBS/1% non-fat dry milk (Bio-RadLaboratories, Hercules, Calif., USA) for 1 hour, and then probed for 1hour at 37° C. with anti-phospho-S6 (Ser 235/236) antibody (CellSignaling Technology, Beverly, Mass., USA, cat. #2211) at 1/200 dilutionin PBS/1% milk/0.3% Tween 20. Wells were then washed twice with PBS, andincubated for 1 hour at 37° C. with PBS/1% milk/0.3% Tween 20+1microg/mL DAPI (4,6-diamidino-2-phenylindole)+1/500 Goat anti-rabbitCy5™-conjugated secondary antibody (Amersham Biosciences, LittleChalfont, Buckinghamshire, UK). Wells were then washed ×2 with PBS, and40 microL PBS are left in each well for immunofluorescence analysis.Fluorescence images in the DAPI and Cy5™ channels were automaticallyacquired, stored and analysed using a Cellomics ArrayScan™ IV instrument(Cellomics, Pittsburgh, USA); the Cellomics Cytotoxicity Algorithm wasused to quantify cytoplasmic fluorescence associated with phospho-S6(Cy5™ signal parameter: “Mean Lyso Mass-pH”) for each cell in 10fields/well, and eventually expressed as a mean population value. Unlessotherwise stated, reagents were obtained from Sigma-Aldrich, St. Louis,Mo., USA.

Biochemical Assay for Inhibitors of Aurora-2 Kinase Activity

The in vitro kinase inhibition assay was conducted in the same way asdescribed for IGF-1R. At variance with IGF-1R, Aurora-2 enzyme does notneed pre-activation.

i. Kinase Buffer (KB) for Aurora-2

The kinase buffer was composed of 50 mM HEPES, pH 7.0, 10 mM MnCl₂, 1 mMDTT, 3 microM Na₃VO₄, and 0.2 mg/mL BSA.

ii. Assay Conditions for Aurora-2 (Final Concentrations)

The kinase assay was run with an enzyme concentration of 2.5 nM, 10microM ATP, 1 nM ³³P-γ-ATP, and 8 microM substrate, composed of 4LRRWSLG repeats.

Cell-Based Assays for Inhibitors of Aurora-2 Kinase Activity In VitroCell Proliferation Assay for Inhibitors of Aurora-2 Kinase Activity

The human colon cancer cell line HCT-116 was seeded at 5000 cells/cm² in24 wells plate (Costar) using F12 medium (Gibco) supplemented with 10%FCS (EuroClone, Italy) 2 mM L-glutamine and 1% penicillin/streptomycinand maintained at 37° C., 5% CO₂ and 96% relative humidity. Thefollowing day, plates were treated in duplicates with 5 mL of anappropriate dilution of compounds starting from a 10 mM stock in DMSO.Two untreated control wells were included in each plate. After 72 hoursof treatment, medium was withdrawn and cells detached from each wellusing 0.5 mL of 0.05% (w/v) Trypsin, 0.02% (w/v) EDTA (Gibco). Sampleswere diluted with 9.5 mL of Isoton (Coulter) and counted using aMultisizer 3 cell counter (Beckman Coulter). Data were evaluated aspercent of the control wells:

% of CTR=(Treated−Blank)/(Control−Blank).

IC₅₀ values were calculated by LSW/Data Analysis using Microsoft Excelsigmoidal curve fitting.

Given the above assays, the compounds of formula (I) of the inventionresulted to possess a remarkable protein kinase inhibitory activity,typically with IC₅₀ lower than 10 μM.

See, as an example, the following Table I reporting the experimentaldata of some representative compounds of the invention being tested inbiochemical assay as ALK, IGF-1R and Aurora-2 kinase inhibitors (IC₅₀μM).

TABLE 1 Cpd ALK IC₅₀ (μM) IGF-1R IC₅₀ (μM) Aur2 IC₅₀ (μM) No.Biochemical assay Biochemical assay Biochemical assay 11 0.055 0.2630.338 4 0.207 2.350 0.484 26 0.411 1.103 0.568 18 1.771 6.070 3.234

From all of the above, the novel compounds of formula (I) of theinvention appear to be particularly advantageous in the therapy ofdiseases caused by deregulated protein kinase activity such as cancer.

The compounds of the present invention can be administered either assingle agents or, alternatively, in combination with known anticancertreatments such as radiation therapy or chemotherapy regimen incombination with, for example, antihormonal agents such asantiestrogens, antiandrogens and aromatase inhibitors, topoisomerase Iinhibitors, topoisomerase II inhibitors, agents that targetmicrotubules, platin-based agents, alkylating agents, DNA damaging orintercalating agents, antineoplastic antimetabolites, other kinaseinhibitors, other anti-angiogenic agents, inhibitors of kinesins,therapeutic monoclonal antibodies, inhibitors of mTOR, histonedeacetylase inhibitors, farnesyl transferase inhibitors, and inhibitorsof hypoxic response.

If formulated as a fixed dose, such combination products employ thecompounds of this invention within the dosage range described below andthe other pharmaceutically active agent within the approved dosagerange.

Compounds of formula (I) may be used sequentially with known anticanceragents when a combination formulation is inappropriate.

The compounds of formula (I) of the present invention, suitable foradministration to a mammal, e.g., to humans, can be administered by theusual routes and the dosage level depends upon the age, weight, andconditions of the patient and administration route.

For example, a suitable dosage adopted for oral administration of acompound of formula (I) may range from about 10 to about 500 mg perdose, from 1 to 5 times daily. The compounds of the invention can beadministered in a variety of dosage forms, e.g., orally, in the formtablets, capsules, sugar or film coated tablets, liquid solutions orsuspensions; rectally in the form suppositories; parenterally, e.g.,intramuscularly, or through intravenous and/or intrathecal and/orintraspinal injection or infusion.

The present invention also includes pharmaceutical compositionscomprising a compound of formula (I) or a pharmaceutically acceptablesalt thereof in association with a pharmaceutically acceptableexcipient, which may be a carrier or a diluent.

The pharmaceutical compositions containing the compounds of theinvention are usually prepared following conventional methods and areadministered in a suitable pharmaceutical form.

For example, the solid oral forms may contain, together with the activecompound, diluents, e.g., lactose, dextrose saccharose, sucrose,cellulose, corn starch or potato starch; lubricants, e.g., silica, talc,stearic acid, magnesium or calcium stearate, and/or polyethyleneglycols; binding agents, e.g., starches, arabic gum, gelatinemethylcellulose, carboxymethylcellulose or polyvinyl pyrrolidone;disintegrating agents, e.g., starch, alginic acid, alginates or sodiumstarch glycolate; effervescing mixtures; dyestuffs; sweeteners; wettingagents such as lecithin, polysorbates, laurylsulphates; and, in general,non-toxic and pharmacologically inactive substances used inpharmaceutical formulations. These pharmaceutical preparations may bemanufactured in known manner, for example, by means of mixing,granulating, tabletting, sugar-coating, or film-coating processes.

The liquid dispersions for oral administration may be, e.g., syrups,emulsions and suspensions.

As an example the syrups may contain, as a carrier, saccharose orsaccharose with glycerine and/or mannitol and sorbitol.

The suspensions and the emulsions may contain, as examples of carriers,natural gum, agar, sodium alginate, pectin, methylcellulose,carboxymethylcellulose, or polyvinyl alcohol.

The suspension or solutions for intramuscular injections may contain,together with the active compound, a pharmaceutically acceptablecarrier, e.g., sterile water, olive oil, ethyl oleate, glycols, e.g.,propylene glycol and, if desired, a suitable amount of lidocainehydrochloride.

The solutions for intravenous injections or infusions may contain, as acarrier, sterile water or preferably they may be in the form of sterile,aqueous, isotonic, saline solutions or they may contain propylene glycolas a carrier.

The suppositories may contain, together with the active compound, apharmaceutically acceptable carrier, e.g., cocoa butter, polyethyleneglycol, a polyoxyethylene sorbitan fatty acid ester surfactant orlecithin.

EXPERIMENTAL SECTION

For a reference to any specific compound of formula (I) of theinvention, optionally in the form of a pharmaceutically acceptable salt,see the experimental section and claims. Referring to the examples thatfollow, compounds of the present invention were synthesized using themethods described herein, or other methods, which are well known in theart.

The short forms and abbreviations used herein have the followingmeaning:

g (grams) mg (milligrams)ml (milliliters) mM (millimolar)μM (micromolar) mmol (millimoles)h (hours) MHz (Mega-Hertz)mm (millimetres) Hz (Hertz)M (molar) min (minutes)mol (moles) TLC (thin layer chromatography)r.t. (room temperature) TEA (triethylamine)TFA (trifluoroacetic acid) DMF (N,N-dimethyl formamide)DIPEA (N,N-diisopropyl-N-ethylamine) DCM (dichloromethane)THF (tetrahydrofuran) Hex (hexane)MeOH (Methanol) DMSO (dimethylsulfoxide)TIPS (triisopropylsilyl) bs (broad singlet)TBDMS (dimethyl-tert-butylsilyl) Ac (acetyl)BOC (tert-butyloxycarbonyl) Ac₂O acetic anhydrideNaH=sodium hydride, 60% in mineral oil ESI=electrospray ionizationTBTU (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluroniumtetrafluoroborateRP-HPLC (reverse phase high performance liquid chromatography) With theaim to better illustrate the present invention, without posing anylimitation to it, the following examples are now given.

As used herein the symbols and conventions used in the processes,schemes and examples are consistent with those used in the contemporaryscientific literature, for example, the Journal of the American ChemicalSociety or the Journal of Biological Chemistry.

Unless otherwise noted, all materials were obtained from commercialsuppliers, of the best grade and used without further purification.Anhydrous solvent such as DMF, THF, CH₂Cl₂ and toluene were obtainedfrom the Aldrich Chemical Company. All reactions involving air- ormoisture-sensitive compounds were performed under nitrogen or argonatmosphere.

General Purification and Analytical Methods

Flash Chromatography was performed on silica gel (Merck grade 9395,60A). HPLC was performed on Waters X Terra RP 18 (4.6×50 mm, 3.5 μm)column using a Waters 2790 HPLC system equipped with a 996 Waters PDAdetector and Micromass mod. ZQ single quadrupole mass spectrometer,equipped with an electrospray (ESI) ion source. Mobile phase A wasammonium acetate 5 mM buffer (pH 5.5 with acetic acid-acetonitrile95:5), and Mobile phase B was water-acetonitrile (5:95). Gradient from10 to 90% B in 8 minutes, hold 90% B 2 minutes. UV detection at 220 nmand 254 nm. Flow rate 1 mL/min. Injection volume 10 microL. Full scan,mass range from 100 to 800 amu. Capillary voltage was 2.5 KV; sourcetemperature was 120° C.; cone was 10 V. Retention times (HPLC r.t.) aregiven in minutes at 220 nm or at 254 nm. Mass are given as m/z ratio.

When necessary, compounds were purified by preparative HPLC on a WatersSymmetry C18 (19×50 mm, 5 um) column or on a Waters X Terra RP 18(30×150 mm, 5 μm) column using a Waters preparative HPLC 600 equippedwith a 996 Waters PDA detector and a Micromass mod. ZMD singlequadrupole mass spectrometer, electron spray ionization, positive mode.Mobile phase A was water-0.01% trifluoroacetic acid, and mobile phase Bwas acetonitrile. Gradient from 10 to 90% B in 8 min, hold 90% B 2 min.Flow rate 20 mL/min. In alternative, mobile phase A was water-0.1% NH₃,and mobile phase B was acetonitrile. Gradient from 10 to 100% B in 8min, hold 100% B 2 min. Flow rate 20 mL/min.

1H-NMR spectrometry was performed on a Mercury VX 400 operating at400.45 MHz equipped with a 5 mm double resonance probe [1H (15N-31P)ID_PFG Varian].

Example 1 Step a5-[(3,5-Difluoro-phenyl)-hydroxy-methyl]-2-fluoro-benzonitrile [(XI),R1═R2═R3═H, R=3,5-difluorophenyl]

To a stirred suspension of magnesium turnings (2.6 g, 109 mmol) inanhydrous tetrahydrofuran under argon (10 mL), a solution of1-bromo-3,5-difluoro-benzene (21 g, 109 mmol) in dry tetrahydrofuran (90mL) was slowly added. The reaction mixture was stirred and heated at 90°C. until all magnesium was consumed (1 hour). Thereafter, the reactionwas cooled at −10° C. and a solution of 2-fluoro-5-formyl-benzonitrile(13.5 g, 90.6 mmol) in 100 mL of anhydrous tetrahydrofuran was addedduring 30 min. After 1 hour, the reaction mixture was quenched by addingdropwise 200 mL of 20% ammonium chloride solution. Ethyl acetate wasadded, the layers were separated, and the aqueous layer was extractedtwice with ethyl acetate. Organic layers were collected, washed withbrine, dried and evaporated. Crude was triturated with isopropylether/hexane 1:1 (100 mL), filtered and washed with the same mixture (50mL) to afford 16 gr of final product. Purification of the resultingorganic phase by chromatography over silica gel (hexane/EtOAc 4:1)afforded 4.5 g of the title compound (total amount 20.5 g, 87% yield).

1H-NMR (400 MHz), δ (ppm, DMSO-d6): 5.82 (d, J=4.02 Hz, 1H) 6.41 (d,J=4.02 Hz, 1H) 7.05-7.12 (m, 1H) 7.12-7.18 (m, 2H) 7.46-7.50 (m, 1H)7.80 (td, J=5.76, 2.62 Hz, 1H) 7.97 (dd, J=6.34, 2.19 Hz, 1H)

Operating in an analogous way, the following compound was obtained:

5-(phenyl-hydroxy-methyl)-2-fluoro-benzonitrile [(XI), R1═R2═R3═H,R=phenyl]

ESI(+) MS: m/z 245 (MNH₄ ⁺).

Step b 5-(3,5-Difluoro-benzoyl)-2-fluoro-benzonitrile [(X), R1═R2═R3═H,R=3,5-difluorophenyl]

A mixture of5-[(3,5-Difluoro-phenyl)-hydroxy-methyl]-2-fluoro-benzonitrile (2.68 g,10.2 mmol), 4-methylmorpholine N-oxide monohydrate (2.02 g, 15 mmol) andtetrapropylammonium perruthenate (35 mg, 0.1 mmol) in drydichloromethane (50 mL) was stirred at room temperature for 2 hours. Thereaction mixture was evaporated and the residue redissolved in ethylacetate. The organic phase was washed with 10% sodium bisulphite andsaturated ammonium chloride, dried and evaporated. Purification of thecrude by chromatography over silica gel (EtOAc/hexane) afforded 2.05 gof the title compound (77% yield).

1H-NMR (400 MHz), δ (ppm, DMSO-d6): 7.43-7.50 (m, 2H) 7.61-7.68 (m, 1H)7.72 (t, J=9.02 Hz, 1H) 8.17 (ddd, J=8.84, 5.30, 2.32 Hz, 1H) 8.35 (dd,J=6.22, 2.20 Hz, 1H)

Operating in an analogous way, the following compound was obtained:

5-Benzoyl-2-fluoro-benzonitrile [(X), R1═R2═R3═H, R=phenyl]

1H-NMR (400 MHz), δ (ppm, DMSO-d6): 7.59 (t, J=7.81 Hz, 2H) 7.72 (m, 2H)7.78 (dd, J=8.30, 1.46 Hz, 2H) 8.13 (ddd, J=8.79, 5.37, 2.20 Hz, 1H)8.28 (dd, J=6.10, 2.20 Hz, 1H)

Step c (3-Amino-1H-indazol-5-yl)-(3,5-difluoro-phenyl)-methanone [(IX),R1═R2═R3═H, R=3,5-difluorophenyl]

A mixture of 5-(3,5-difluoro-benzoyl)-2-fluoro-benzonitrile (2.05 g,7.84 mmol) and hydrazine hydrate (0.73 mL, 15.7 mmol) in drytetrahydrofuran (100 mL) was stirred at room temperature for 2 hours.The reaction mixture was treated with 37% hydrochloric acid (1.3 mL,15.7 mmol) for 30 min and then the volatiles were partially evaporated.The reaction mixture was then diluted with water (100 mL) and aqueousNH₃ was added to reach neutral pH. The resulting solid was filtered,washed thoroughly with water and dried under vacuum at 60° C. The titlecompound was obtained as yellow solid (1.75 g, 80% yield).

1H-NMR (400 MHz), δ (ppm, DMSO-d6): 5.75 (br. s., 2H) 7.33-7.36 (m, 1H)7.36-7.40 (m, 2H) 7.52-7.59 (m, 1H) 7.75 (dd, J=8.84, 1.65 Hz, 1H) 8.27(dd, J=1.59, 0.73 Hz, 1H) 11.95 (br. s., 1H)

Operating in an analogous way, the following compounds were obtained:

(3-Amino-1H-indazol-5-yl)-(3-ethoxy-phenyl)-methanone [(IX), R1═R2═R3═H,R=3-ethoxyphenyl]

1H-NMR (400 MHz), δ (ppm, DMSO-d6): 1.36 (t, J=7.01 Hz, 3H) 4.11 (q,J=6.95 Hz, 2H) 7.20-7.24 (m, 2H) 7.25-7.28 (m, 1H) 7.41 (dd, J=8.84,0.55 Hz, 1H) 7.48 (td, J=7.68, 0.61 Hz, 1H) 7.80 (dd, J=8.78, 1.59 Hz,1H) 8.34 (d, J=0.85 Hz, 1H) 12.24 (br. s., 1H)

(3-Amino-1H-indazol-5-yl)-phenyl-methanone [(IX), R1═R2═R3═H, R=phenyl]

1H-NMR (400 MHz), δ (ppm, DMSO-d6): 7.40 (dd, J=8.78, 0.61 Hz, 1H) 7.57(tt, J=7.68, 1.59 Hz, 2H) 7.66 (tt, J=7.32, 2.07 Hz, 1H) 7.72 (dt,J=6.83, 1.34 Hz, 2H) 7.78 (dd, J=8.78, 1.59 Hz, 1H) 8.31 (m, 1H) 12.15(br. s., 1H)

Step dN-[5-(3,5-Difluoro-benzoyl)-1H-indazol-3-yl]-2,2,2-trifluoro-acetamide[(VIII), R1═R2═R3═H, R=3,5-difluorophenyl, PG₁=trifluoroacethyl]

A suspension of(3-amino-1H-indazol-5-yl)-(3,5-difluoro-phenyl)-methanone (2.73 g, 10mmol) in dry tetrahydrofuran (120 mL) was treated with trifluoroaceticanhydride (4.2 mL, 30 mmol) and stirred 1 hour at room temperature. Thesolution was evaporated, treated with methanol and further evaporated todryness. The residue was redissolved in ethyl acetate and washed withaqueous bicarbonate. The organic phase was separated, dried andevaporated. The solid was triturated with a small amount ofdichloromethane and filtered affording 3.25 g (88% yield) of titlecompound.

1H-NMR (400 MHz), δ (ppm, DMSO-d6): 7.39-7.46 (m, 2H) 7.56-7.64 (m, 1H)7.68 (dd, J=8.84, 0.67 Hz, 1H) 7.86 (dd, J=8.84, 1.65 Hz, 1H) 8.28-8.32(m, 1H) 12.16 (s, 1H) 13.50 (s, 1H)

Operating in an analogous way, the following compound was obtained:

N-[5-(3-Ethoxy-benzoyl)-1H-indazol-3-yl]-2,2,2-trifluoro-acetamide[(VIII), R1═R2═R3═H, R=3-ethoxyphenyl, PG₁=trifluoroacethyl]

1H-NMR (400 MHz), δ (ppm, DMSO-d6): 1.34 (t, J=6.95 Hz, 3H) 4.10 (q,J=6.95 Hz, 2H) 7.19-7.25 (m, 2H) 7.28 (d, J=7.56 Hz, 1H) 7.43-7.50 (m,1H) 7.67 (d, J=8.90 Hz, 1H) 7.85 (dd, J=8.84, 1.52 Hz, 1H) 8.26 (s, 1H)12.14 (s, 1H) 13.46 (s, 1H)

Step eN-[5-(3,5-Difluoro-benzoyl)-1-trityl-1H-indazol-3-yl]-2,2,2-trifluoro-acetamide[(VII), R1═R2═R3═H, R=3,5-difluorophenyl, PG=triphenylmethyl,PG₁=trifluoroacethyl]

N-[5-(3,5-Difluoro-benzoyl)-1H-indazol-3-yl]-2,2,2-trifluoro-acetamide(19.11 g, 51.76 mmol) in dry dichloromethane (300 mL) was treated withchlorotriphenylmethane (14.72 g, 52.8 mmol) and triethylamine (14.55 mL,103.5 mmol). After stirring at room temperature for two days, thereaction was washed with a solution of NH₄Cl, dried and evaporated.Purification of the crude by chromatography over silica gel (DCM/MeOH)afforded 27.32 g of the title compound (86% yield).

1H-NMR (400 MHz), δ (ppm, DMSO-d6): 6.57 (d, J=8.90 Hz, 1H) 7.20 (m, 6H)7.29-7.40 (m, 11H) 7.58 (m, 2H) 8.22 (d, J=1.10 Hz, 1H) 12.27 (s, 1H)

Operating in an analogous way, the following compound was obtained:

N-[5-(3-Ethoxy-benzoyl)-1-trityl-1H-indazol-3-yl]-2,2,2-trifluoro-acetamide[(VII), R1═R2═R3═H, R=3-ethoxyphenyl, PG=triphenylmethyl,PG₁=trifluoroacethyl]

1H-NMR (400 MHz), δ (ppm, DMSO-d6): 1.33 (t, J=6.95 Hz, 3H) 4.10 (q,J=6.95 Hz, 2H) 6.56 (d, J=9.02 Hz, 1H) 7.17-7.39 (m, 18H) 7.41-7.47 (m,1H) 7.54 (dd, J=9.08, 1.65 Hz, 1H) 8.18 (d, J=0.98 Hz, 1H) 12.25 (s, 1H)

Step f(3-Amino-1-trityl-1H-indazol-5-yl)-(3,5-difluoro-phenyl)-methanone[(VI), R1═R2═R3═H, R=3,5-difluorophenyl, PG=triphenylmethyl]

N-[5-(3,5-Difluoro-benzoyl)-1-trityl-1H-indazol-3-yl]-2,2,2-trifluoro-acetamide(6.12 g, 10 mmol) was heated at 100° C. in a mixtureisopropanol/tetrahydrofuran 8:2 (100 mL) and triethylamine (12.2 mL) for48 hours. The volatiles were partially evaporated and the resultingmixture cooled and filtered. The solid was washed with diethyl ether.After drying under vacuum at 70° C. the title compound was obtained as awhite solid (5.1 g, 99% yield).

1H-NMR (400 MHz), δ (ppm, DMSO-d6): 5.98 (br. s., 2H) 6.35 (d, J=8.90Hz, 1H) 7.20-7.37 (m, 17H) 7.48 (dd, J=9.08, 1.77 Hz, 1H) 7.50-7.57 (m,1H) 8.23 (d, J=1.10 Hz, 1H)

Operating in an analogous way, the following compound was obtained:

(3-Amino-1-trityl-1H-indazol-5-yl)-(3-ethoxy-phenyl)-methanone [(VI),R1═R2═R3═H, R=3-ethoxyphenyl, PG=triphenylmethyl]

1H-NMR (400 MHz), δ (ppm, DMSO-d6): 1.33 (t, J=6.95 Hz, 3H) 4.07 (q,J=6.95 Hz, 2H) 5.93 (s, 2H) 6.36 (d, J=9.02 Hz, 1H) 7.12-7.34 (m, 18H)7.40-7.46 (m, 2H) 8.22 (d, J=1.10 Hz, 1H)

Step gN-[5-(3,5-Difluoro-benzoyl)-1-trityl-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl-2-nitro-benzamide[(V), R1═R2═R3═H, R=3,5-difluorophenyl,Ar=4-(4-methyl-piperazin-1-yl)-2-nitro-phenyl, PG=triphenylmethyl]

To a suspension of 4-(4-methyl-piperazin-1-yl)-2-nitro-benzoic acidhydrochloride (1.5 g, 4.97 mmol) in dry tetrahydrofuran (80 mL) wereadded oxalyl chloride (1.4 mL, 19.9 mmol) and N,N-dimethylformamide (1-2drops). The mixture was stirred at room temperature overnight and thenevaporated to dryness. The resulting crude acyl chloride was taken-upwith toluene and evaporated again then dissolved in dry tetrahydrofuran(180 mL). A solution of(3-amino-1-trityl-1H-indazol-5-yl)-(3,5-difluoro-phenyl)-methanone (1.83g. 3.55 mmol) and N,N-diisopropylethylamine (2.5 mL, 14.22 mmol) in drytetrahydrofuran (15 mL) was added to the reaction mixture. The mixturewas stirred at room temperature overnight and then at 75° C. for 2hours. The volatiles were evaporated and the residue taken up withdichloromethane and washed with brine. The organic phase was dried oversodium sulfate and evaporated to dryness. Purification of the crude bychromatography over silica gel (DCM/MeOH) afforded 2.51 g of the titlecompound as yellow powder (92% yield).

1H-NMR (400 MHz), δ (ppm, DMSO-d6): 2.22 (s, 3H) 2.40-2.45 (m, 4H)3.26-3.36 (m, 4H) 6.50 (d, J=8.17 Hz, 1H) 7.19-7.50 (m, 21H) 7.56 (dd,J=9.15, 1.71 Hz, 1H) 8.28-8.30 (m, 1H) 11.22 (br. s., 1H)

Operating in an analogous way, the following compound was obtained:

N-[5-(3-Ethoxy-benzoyl)-1-trityl-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-nitro-benzamide[(V), R1═R2═R3═H, R=3-ethoxyphenyl,Ar=4-(4-methyl-piperazin-1-yl)-2-nitro-phenyl, PG=triphenylmethyl]

1H-NMR (400 MHz), δ (ppm, DMSO-d6): 1.34 (t, J=6.95 Hz, 3H) 2.24 (m, 3H)2.45 (m, 4H) 3.27 (m, 4H) 4.08 (q, J=6.95 Hz, 2H) 6.51 (d, J=8.17 Hz,1H) 7.20-7.46 (m, 22H) 7.53 (dd, J=9.15, 1.71 Hz, 1H) 8.30 (m, 1H) 11.22(br. s., 1H)

Step hN-[5-(3,5-Difluoro-benzoyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-nitro-benzamide[(II), R1═R2═R3═H, R=3,5-difluorophenyl,Ar=4-(4-methyl-piperazin-1-yl)-2-nitro-phenyl]

A mixture ofN-[5-(3,5-Difluoro-benzoyl)-1-trityl-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-nitro-benzamide(2.76 g, 3.62 mmol), trifluoroacetic acid (5.6 mL) and dichloromethane(56 mL) was stirred at room temperature for 2 hours. The volatiles wereevaporated and the residue taken up with dichloromethane and washed witha saturated solution of sodium hydrogen-carbonate. The organic phase wasevaporated to dryness. The residue was redissolved in ethyl acetate andwashed twice with brine. The resulting organic phase was dried oversodium sulfate and evaporated to dryness. Purification of the crude bychromatography over silica gel (DCM/MeOH) and trituration of the soobtained compound from diethyl ether afforded 1.47 g of the titlecompound (78% yield).

1H-NMR (400 MHz), δ (ppm, DMSO-d6): 2.25 (br. s., 3H) 2.47 (br. s., 4H)3.29-3.38 (m, 4H) 7.26 (dd, J=8.84, 2.50 Hz, 1H) 7.37-7.43 (m, 2H) 7.45(d, J=2.44 Hz, 1H) 7.51-7.59 (m, 1H) 7.63 (dd, J=8.84, 0.55 Hz, 1H) 7.66(br. s., 1H) 7.86 (dd, J=8.84, 1.65 Hz, 1H) 8.36 (s, 1H) 11.13 (s, 1H)13.21 (s, 1H)

Operating in an analogous way, the following compounds were obtained:

N-[5-(3-Ethoxy-benzoyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-nitro-benzamide[(II), R1═R2═R3═H, R=3-ethoxyphenyl,Ar=4-(4-methyl-piperazin-1-yl)-2-nitro-phenyl]

1H-NMR (400 MHz), δ (ppm, DMSO-d6): 1.34 (t, J=6.95 Hz, 3H) 2.26-2.34(m, 3H) 2.46-2.59 (m, 4H) 3.28-3.35 (m, 4H) 4.10 (q, J=6.95 Hz, 2H)7.18-7.21 (m, 1H) 7.24-7.26 (m, 1H) 7.27 (dd, J=9.33, 1.89 Hz, 1H)7.29-7.32 (m, 1H) 7.45 (t, J=7.87 Hz, 1H) 7.46 (d, J=2.32 Hz, 1H) 7.62(d, J=9.02 Hz, 1H) 7.66 (d, J=9.88 Hz, 1H) 7.84 (dd, J=8.78, 1.59 Hz,1H) 8.39 (s, 1H) 11.13 (br. s., 1H) 13.17 (s, 1H)

4-[(3-Dimethylamino-propyl)-methyl-amino]-N-[5-(3-ethoxy-benzoyl)-1H-indazol-3-yl]-2-nitro-benzamide[(II), R1═R2═R3═H, R=3-ethoxyphenyl,Ar=4-[(3-dimethylamino-propyl)-methyl-amino]-2-nitro-phenyl]

1H-NMR (400 MHz), δ (ppm, DMSO-d6): 1.33 (t, J=6.95 Hz, 3H) 1.60-1.78(m, 2H) 2.22 (s, 6H) 2.29-2.37 (m, 2H) 3.01 (s, 3H) 3.48 (t, J=7.01 Hz,2H) 4.09 (q, J=6.99 Hz, 2H) 6.98 (dd, J=8.84, 2.50 Hz, 1H) 7.16-7.21 (m,2H) 7.22-7.25 (m, 1H) 7.27-7.32 (m, 1H) 7.45 (t, J=7.93 Hz, 1H)7.58-7.66 (m, 2H) 7.83 (dd, J=8.78, 1.59 Hz, 1H) 8.36 (s, 1H) 11.04 (s,1H) 13.14 (s, 1H)

Step iN-[5-(3,5-Difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-nitro-benzamide[(I_(A)), R1═R2═R3═H, R=3,5-difluorophenyl,Ar=4-(4-methyl-piperazin-1-yl)-2-nitro-phenyl] cpd. 6

N-[5-(3,5-Difluoro-benzoyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-nitro-benzamide(3.61 g, 6.93 mmol) was dissolved in DCM (150 mL) in argon atmosphereand trifluoroacetic acid (150 mL) is added under stirring. Sodiumborohydride pellets (2.62 gr, 69.3 mmol) is gradually added over aperiod of 72 hours. The reaction mixture was evaporated, taken up with amixture MeOH/acetone and stirred for 1 hour. The resulting mixture wasevaporated to dryness, redissolved in MeOH and NaOH 8N was added tillbasic pH was reached. Crude was evaporated and ice/water was added, thesolid thus formed was filtered, washed with water and dried under vacuumat 80° C. affording 3.22 g of title compound (92% yield).

1H-NMR (400 MHz), δ (ppm, DMSO-d6): 2.23 (s, 3H) 2.42-2.47 (m, 4H)3.33-3.38 (m, 4H) 4.05 (s, 2H) 6.91-6.97 (m, 2H) 6.97-7.05 (m, 1H) 7.24(dd, J=8.60, 1.52 Hz, 1H) 7.27 (br. s., 1H) 7.41 (d, J=8.66 Hz, 1H) 7.44(br. s., 1H) 7.63 (s, 1H) 7.66-7.73 (m, 1H) 10.81 (br. s., 1H) 12.70 (s,1H)

Operating in an analogous way, the following compounds were obtained:

4-[(3-Dimethylamino-propyl)-methyl-amino]-N-[5-(3-ethoxy-benzyl)-1H-indazol-3-yl]-2-nitro-benzamide[(I_(A)), R1═R2═R3═H, R=3-ethoxyphenyl,Ar=4-[(3-dimethylamino-propyl)-methyl-amino]-2-nitro-phenyl] cpd. 53

1H-NMR (400 MHz), δ (ppm, DMSO-d6): 1.26-1.31 (m, 3H) 1.69 (t, J=6.77Hz, 2H) 2.19 (s, 6H) 2.28 (br. s., 2H) 3.02 (s, 3H) 3.45-3.51 (m, 2H)3.93-4.00 (m, 2H) 3.96 (s, 2H) 6.70-6.73 (m, 1H) 6.76-6.80 (m, 1H) 6.77(d, J=1.59 Hz, 1H) 6.98 (d, J=8.90 Hz, 1H) 7.14-7.19 (m, 1H) 7.19-7.23(m, 2H) 7.38 (d, J=8.66 Hz, 1H) 7.61 (s, 1H) 7.67 (d, J=10.00 Hz, 1H)10.72 (br. s., 1H) 12.65 (s, 1H)

N-{5-[(3,5-Difluoro-phenyl)-hydroxy-methyl]-1H-indazol-3-yl}-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide[(I_(B)), R1═R2═R3═H, R=3,5-difluorophenyl,Ar=4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-phenyl]cpd. 60

A mixture ofN-[5-(3,5-Difluoro-benzoyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide(130 mg, 0.226 mmol) and sodium borohydride (15 mg, 0.39 mmol) wasdissolved at room temperature in i-propanol (20 mL). The reactionmixture was stirred for 4 hours, quenched with methanol and evaporatedto dryness. Crude material was redissolved in DCM and washed with brine.After trituration with diethyl ether, 59 mg of the title compound wererecovered (45% yield).

1H-NMR (400 MHz), δ (ppm, DMSO-d6): 1.26-1.41 (m, 2H) 1.89-1.99 (m, 2H)2.23 (s, 3H) 2.39-2.47 (m, 4H) 3.21-3.29 (m, 4H) 3.45-3.55 (m, 2H)3.63-3.74 (m, 1H) 3.76-3.86 (m, 2H) 5.81 (d, J=4.15 Hz, 1H) 6.12 (d,J=4.15 Hz, 1H) 6.14 (d, J=2.07 Hz, 1H) 6.24 (dd, J=9.08, 2.26 Hz, 1H)6.96-7.04 (m, 1H) 7.05-7.12 (m, 2H) 7.27-7.36 (m, 1H) 7.37-7.43 (m, 1H)7.64 (s, 1H) 7.80 (d, J=9.15 Hz, 1H) 8.31 (d, J=7.56 Hz, 1H) 10.09 (s,1H) 12.63 (s, 1H)

N-{5-[(3-Ethoxy-phenyl)-hydroxy-methyl]-1H-indazol-3-yl}-4-(4-methyl-piperazin-1-yl)-2-nitro-benzamide[(I_(B)), R1═R2═R3═H, R=3-ethoxyphenyl,Ar=4-(4-methyl-piperazin-1-yl)-2-nitro-phenyl] cpd. 67

1H-NMR (400 MHz), δ (ppm, DMSO-d6): 1.29 (t, J=6.95 Hz, 3H) 2.24 (s, 3H)2.42-2.47 (m, 4H) 3.36 (m, 4H) 3.97 (q, J=6.95 Hz, 2H) 5.70 (d, J=3.90Hz, 1H) 5.85 (d, J=3.90 Hz, 1H) 6.72 (ddd, J=8.17, 2.56, 0.73 Hz, 1H)6.90 (d, J=7.68 Hz, 1H) 6.93 (dd, J=2.20, 1.46 Hz, 1H) 7.17 (t, J=7.87Hz, 1H) 7.26 (d, J=8.78 Hz, 1H) 7.28 (dd, J=8.72, 1.40 Hz, 1H) 7.36 (d,J=8.78 Hz, 1H) 7.44 (d, J=2.07 Hz, 1H) 7.70 (d, J=6.71 Hz, 1H) 7.81 (br.s., 1H) 10.80 (br. s., 1H) 12.65 (s, 1H).

Example 2 Step j 5-(3,5-Difluoro-benzyl)-2-fluoro-benzonitrile [(XIV),R1═R2═R3═H, R=3,5-difluorophenyl]

5-[(3,5-Difluoro-phenyl)-hydroxy-methyl]-2-fluoro-benzonitrile (3.5 g,13.3 mmol) and sodium iodide (20 g, 133 mmol) are stirred inacetonitrile (50 mL) under nitrogen at 60° C. To the reaction mixture isgradually added chlorotrimethylsilane (17 mL, 134 mmol) over a period of8 hours. The mixture is diluted with ethyl acetate and washed withwater, saturated aquoeus sodium bicarbonate, 10% aquoeus sodiumthiosulfate and brine. Purification of the crude by chromatography oversilica gel (EtOAc/hexane 5:100) afforded 3.1 g of the title compound(88% yield).

1H-NMR (400 MHz), δ (ppm, DMSO-d6): 4.02 (s, 2H) 7.02-7.11 (m, 3H) 7.47(t, J=9.08 Hz, 1H) 7.68-7.74 (m, 1H) 7.90 (dd, J=6.22, 2.19 Hz, 1H)

Operating in an analogous way, the following compound was obtained:

5-benzyl-2-fluoro-benzonitrile [(XIV), R1═R2═R3═H, R=phenyl]

ESI(+) MS: m/z 229 (MNH₄ ⁺).

Step k 5-(3,5-Difluoro-benzyl)-2-fluoro-benzonitrile [(XIV), R1═R2═R3═H,R=3,5-difluorophenyl]

3-Cyano-4-fluorophenylboronic acid (1.649 g, 10 mmol), powderedpotassium phosphate (4.254 g, 20 mmol) and Pd(PPh₃)₄ (231 mg, 0.2 mmol)were charged in an oven-dried flask under argon atmosphere. The flaskwas evacuated and back-filled with argon thrice and then toluene (30 mL)and 3,5-difluorobenzyl bromide (1.295 mL, 10 mmol) were added by meansof a syringe through a lattice stopper, under good stirring.

The reaction mixture was heated to 100° C. in half an hour andmaintained at that temperature for 1.5 hours. The black mixture wastaken up with diethylether (200 mL), washed with saturated aqueousamonium chloride (2×20 mL), brine (3×30 mL), dried over sodium sulphateand evaporated to dryness to afford 3.21 g of yellow oil. The crude waspurified by flash chromatography on silica gel eluting withn-hexane/ethyl acetate 95:5 to yield 1.89 g (yield 76.4%) of whitishsolid.

1H-NMR (400 MHz), δ (ppm, DMSO-d6): 4.02 (s, 2H) 7.02-7.11 (m, 3H) 7.47(t, J=9.08 Hz, 1H) 7.68-7.74 (m, 1H) 7.90 (dd, J=6.22, 2.19 Hz, 1H)

Following an analogous procedure the compounds listed below wereprepared:

5-(2,5-Difluoro-benzyl)-2-fluoro-benzonitrile

1H-NMR (400 MHz), δ (ppm, DMSO-d6): 4.01 (s, 2H), 7.09-7.17 (m, 1H),7.20-7.27 (m, 2H), 7.46 (t, J=9.08 Hz, 1H), 7.64 (m, 1H), 7.82 (dd,J=6.22, 2.19 Hz, 1H)

2-Fluoro-5-(5-fluoro-2-methyl-benzyl)-benzonitrile

1H-NMR (400 MHz), δ (ppm, DMSO-d6): 2.18 (s, 3H), 4.01 (s, 2H), 7.00 (m,2H), 7.22 (m, 1H), 7.48 (t, J=9.08 Hz, 1H), 7.56 (m, 1H), 7.75 (dd,J=6.22, 2.19 Hz, 1H)

2-Fluoro-5-(3-fluoro-benzyl)-benzonitrile

1H-NMR (400 MHz), δ (ppm, DMSO-d6): 3.98 (s, 2H), 6.95-7.15 (m, 3H),7.27-7.38 (m, 1H), 7.38-7.48 (t, 1H), 7.61-7.70 (m, 1H), 7.81-7.87 (dd,J=6.22, 2.19 Hz. 1H).

2-Fluoro-5-pyridin-3-ylmethyl-benzonitrile

1H-NMR (400 MHz), δ (ppm, DMSO-d6): 4.03 (s, 2H) 7.33 (ddd, J=7.83,4.79, 0.79 Hz, 1H) 7.47 (t, J=9.02 Hz, 1H) 7.65-7.68 (m, 1H) 7.68-7.72(m, 1H) 7.89 (dd, J=6.28, 2.01 Hz, 1H) 8.44 (dd, J=4.76, 1.59 Hz, 1H)8.54 (d, J=1.71 Hz, 1H)

Step l 5-(3,5-Difluoro-benzyl)-1H-indazol-3-ylamine [(III_(A)),R1═R2═R3═H, R=3,5-difluorophenyl]

A mixture of 5-(3,5-difluoro-benzyl)-2-fluoro-benzonitrile (20 g, 80.9mmol) and hydrazine hydrate (19.6 mL, 404 mmol) in n-butanol (200 mL)was heated at 120° C. overnight. The reaction mixture was diluted withwater/ethyl acetate and the organic phase washed twice with brine, driedand evaporated. Crude was triturated with diethyl ether and filtered toafford 13 gr of final product. Purification of the resulting organicphase by chromatography over silica gel (DCM/EtOH 95:5) afforded further6.3 g of the title compound (total amount 19.2 g, 92% yield).

1H-NMR (400 MHz), δ (ppm, DMSO-d6): 4.01 (s, 2H) 5.23 (s, 2H) 6.89-6.98(m, 2H) 7.03 (tt, J=9.43, 2.33 Hz, 1H) 7.11-7.15 (m, 1H) 7.16-7.20 (m,1H) 7.53 (s, 1H) 11.30 (s, 1H)

Following an analogous procedure the compounds listed below wereprepared:

5-(2,5-Difluoro-benzyl)-1H-indazol-3-ylamine

1H-NMR (400 MHz), δ (ppm, DMSO-d6): 3.99 (s, 2H), 5.28 (m, 2H),7.05-7.25 (m, 5H), 7.51 (s, 1H), 11.30 (bs, 1H).

5-(5-Fluoro-2-methyl-benzyl)-1H-indazol-3-ylamine

1H-NMR (400 MHz), δ (ppm, DMSO-d6): 2.21 (s, 3H), 3.97 (s, 2H), 5.22(bs, 2H), 7.43 (s, 1H), 7.14-7.20 (m, 2H), 7.06 (dd, 1H), 6.87-6.97 (m,2H), 11.27 (bs, 1H).

5-(3-Fluoro-benzyl)-1H-indazol-3-ylamine

1H-NMR (400 MHz), δ (ppm, DMSO-d6): 4.00 (s, 2H), 5.22 (bs, 2H),6.96-7.09 (m, 3H), 7.11 (m, 1H), 7.15 (m, 1H), 7.29-7.37 (m, 1H), 7.53(s, 1H), 11.27 (s, 1H).

5-Pyridin-3-ylmethyl-1H-indazol-3-ylamine

1H-NMR (400 MHz), δ (ppm, DMSO-d6): 4.01 (s, 2H) 5.23 (br. s., 2H)7.08-7.15 (m, 1H) 7.15-7.19 (m, 1H) 7.25-7.34 (m, 1H) 7.53 (s, 1H) 7.60(dt, J=7.86, 1.92 Hz, 1H) 8.40 (dd, J=4.69, 1.65 Hz, 1H) 8.51 (d, J=1.83Hz, 1H) 11.28 (s, 1H)

5-benzyl-1H-indazol-3-ylamine

1H-NMR (400 MHz), δ (ppm, DMSO-d6): 3.97 (s, 2H) 5.21 (s, 2H) 7.07-7.11(m, 1H) 7.13-7.16 (m, 1H) 7.16-7.20 (m, 1H) 7.20-7.24 (m, 2H) 7.25-7.31(m, 2H) 7.52 (s, 1H) 11.25 (s, 1H).

Step n 5-[1-(3,5-Difluoro-phenyl)ethyl]-2-fluoro-benzonitrile [(XIXD₁),R1═R2═R3═H, R=3,5-difluorophenyl, R′=methyl]

5-(3,5-Difluoro-benzyl)-2-fluoro-benzonitrile (450 mg, 1.82 mmol) wasdissolved in THFdry (14 mL) in nitrogen atmosphere at −20° C. and methyliodide (0.17 mL, 2.73 mmol) was added under stirring.Bis-(trimethylsilyl)-lithiumamid, 1.0 M in THF (0.684 ml, 3.64 mmol) wasgradually added. After 20 minutes the reaction was quenched by adding asolution of KHSO₄ 10% and extracted with ethyl acetate. The organicphase was washed with aqueous KHSO₄ 10% and brine, dried over sodiumsulfate and evaporated to dryness. The crude was purified by flashchromatography on silica gel using hexane/ethyl acetate 98/2 as theeluant. The title product was isolated as an oil (400 mg, 84% yield).

1H-NMR (400 MHz), δ (ppm, DMSO-d6): 1.59 (d, J=7.32 Hz, 3H) 4.31 (q,J=7.19 Hz, 1H) 7.08 (m, 3H) 7.46 (t, J=9.15 Hz, 1H) 7.73 (m, 1H) 7.95(dd, J=6.22, 2.44 Hz, 1H)

Step l′″ 5-[1-(3,5-Difluoro-phenyl)-ethyl]-1H-indazol-3-ylamine[(IIID₁), R1═R2═R3═H, R=3,5-difluorophenyl, R′=methyl]

5-[1-(3,5-Difluoro-phenyl)-ethyl]-2-fluoro-benzonitrile (324 mg, 1.24mmol) was dissolved in n-butanol (3 mL) and hydrazine hydrate (0.301 mL,6.20 mmol) was added. The reaction mixture was stirred at 120° C. for 22hours then quenched by adding water/ethyl acetate. The organic phaseseparated was washed with water and brine, dried over sodium sulfate andevaporated to dryness. The crude was purified by chromatography onsilica gel with a gradient elution of DCM/EtOH from 99/1 to 98/2. Titleproduct was isolated as an oil (96 mg, 39% yield).

1H-NMR (400 MHz), δ (ppm, DMSO-d6): 1.61 (d, J=7.19 Hz, 3H) 4.25 (q,J=7.32 Hz, 1H) 5.26 (br. s, 5.26, 2H) 6.99 (m, 3H) 7.12 (dd, J=8.66,1.59 Hz, 1H) 7.16 (dd, J=8.54, 0.73 Hz, 1H) 7.62 (br. s, 1H) 11.29 (s,1H)

Step i′N-[5-(3,5-Difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide[(I_(A)), R1═R2═R3═H, R=3,5-difluorophenyl,Ar=4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-phenyl]cpd. 11

To a suspension of4-(4-methyl-piperazin-1-yl)-2-[(tetrahydro-pyran-4-yl)-(2,2,2-trifluoro-acetyl)-amino]-benzoicacid trifluoroacetate (10 g, 22.1 mmol) in dry dichloromethane (300 mL)oxalyl chloride (3.58 mL, 42.3 mmol) and N,N-dimethylformamide (1-2drops) were added. The mixture was stirred at room temperature for 2hours then evaporated to dryness. The resulting crude acyl chloride wastaken-up with toluene and evaporated again then dissolved in drytetrahydrofuran (130 mL) at −20° C. A solution of5-(3,5-difluoro-benzyl)-1H-indazol-3-ylamine (5 g. 19.28 mmol) andN,N-diisopropylethylamine (12.8 mL, 73.3 mmol) in dry THF (40 mL) wasadded to the cooled reaction mixture. The mixture was stirred at −20° C.for 4 hours then quenched by adding water/ethyl acetate. The organicphase was washed with a saturated solution of sodium hydrogenocarbonate,dried over sodium sulfate and evaporated to dryness.

The crude can be purified by flash chromatography on silica gel usingdichloromethane/ethanol 100:10 as the eluant, affording intermediateN-[5-(3,5-Difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-[(tetrahydro-pyran-4-yl)-(2,2,2-trifluoro-acetyl)-amino]-benzamideas a pale yellow solid.

1H-NMR (400 MHz), δ (ppm, DMSO-d6): 1.25-1.41 (m, 1H) 1.48-1.61 (m, 1H)1.66 (d, J=9.02 Hz, 1H) 1.92 (d, J=9.15 Hz, 1H) 2.25 (s, 3H) 2.43-2.49(m, 4H) 3.23-3.41 (m, 6H) 3.77 (dd, J=10.91, 4.21 Hz, 1H) 3.87 (dd,J=11.65, 3.96 Hz, 1H) 4.02 (s, 2H) 4.37-4.49 (m, 1H) 6.89 (d, J=2.44 Hz,1H) 6.90-6.98 (m, 2H) 7.02 (tt, J=9.42, 2.29 Hz, 1H) 7.09 (dd, J=8.78,2.44 Hz, 1H) 7.27 (dd, J=8.72, 1.40 Hz, 1H) 7.41-7.43 (m, 2H) 7.83 (d,J=8.78 Hz, 1H) 10.52 (s, 1H) 12.69 (s, 1H)

Alternatively, not previously purified crude reaction mixture can bedissolved in methanol (375 mL) in the presence of triethylamine (60 mL)and stirred at 65° C. for 2 hours. The solvents were removed underreduced pressure and the residue treated with water/ethyl acetate.Organic phase was dried over sodium sulfate and evaporated to dryness.Purification of the crude by chromatography over silica gel(DCM/EtOH/NH₃ 5N in MeOH=1000/50/5) and crystallisation of the soobtained compound from EtOAc/hexane afforded 8.4 g of the title compoundas a white solid (78% yield).

1H-NMR (400 MHz), δ (ppm, DMSO-d6): 1.26-1.43 (m, 2H) 1.86-2.02 (m, 2H)2.23 (s, 3H) 2.42-2.46 (m, 4H) 3.23-3.29 (m, 4H) 3.45-3.54 (m, 2H)3.62-3.75 (m, 1H) 3.82 (dt, J=11.61, 3.83 Hz, 2H) 4.05 (s, 2H) 6.14 (d,J=2.07 Hz, 1H) 6.24 (dd, J=8.90, 2.19 Hz, 1H) 6.94-7.06 (m, 3H) 7.26(dd, J=8.66, 1.46 Hz, 1H) 7.41 (d, J=8.66 Hz, 1H) 7.50 (d, 1H) 7.80 (d,J=9.15 Hz, 1H) 8.29 (d, J=7.68 Hz, 1H) 10.08 (s, 1H) 12.63 (s, 1H).

Operating in an analogous way, the following compounds were obtained:

N-[5-(3,5-Difluoro-benzyl)-1H-indazol-3-yl]-2-(3-methoxy-propylamino)-4-(4-methyl-piperazin-1-yl)-benzamide[(I_(A)), R1═R2═R3═H, R=3,5-difluorophenyl,Ar=4-(4-methyl-piperazin-1-yl)-2-(3-methoxy-propylamino)-phenyl] cpd. 36

1H-NMR (400 MHz), δ (ppm, DMSO-d6): 1.80 (quin, J=6.49 Hz, 2H) 2.24 (s,3H) 2.42-2.47 (m, 4H) 3.16-3.21 (m, 2H) 3.23 (s, 3H) 3.26-3.32 (m, 4H)3.41 (t, J=6.16 Hz, 2H) 4.04 (s, 2H) 6.07 (d, J=2.19 Hz, 1H) 6.24 (dd,J=9.02, 2.19 Hz, 1H) 6.95-7.00 (m, 2H) 6.99-7.04 (m, 1H) 7.24 (dd,J=8.66, 1.59 Hz, 1H) 7.41 (d, J=8.54 Hz, 1H) 7.51 (s, 1H) 7.80 (d,J=9.15 Hz, 1H) 8.19 (t, J=5.12 Hz, 1H) 10.07 (s, 1H) 12.62 (s, 1H)

N-[5-(3,5-Difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-benzamide[(I_(A)),R1═R2═R3═H, R=3,5-difluorophenyl, Ar=4-(4-methyl-piperazin-1-yl)-phenyl]cpd. 4

1H-NMR (400 MHz), δ (ppm, DMSO-d6): 2.23 (s, 3H) 2.44-2.49 (m, 4H)3.28-3.32 (m, 4H) 4.05 (s, 2H) 6.90-7.00 (m, 3H) 7.02 (d, J=9.15 Hz, 2H)7.24 (dd, J=8.66, 1.59 Hz, 1H) 7.41 (d, J=0.49 Hz, 1H) 7.59 (s, 1H) 7.97(d, J=9.02 Hz, 2H) 10.39 (s, 1H) 12.67 (s, 1H)

N-[5-(3,5-Difluoro-benzyl)-1H-indazol-3-yl]-2-((R)-2-methoxy-1-methyl-ethylamino)-4-(4-methyl-piperazin-1-yl)-benzamide[(I_(A)), R1═R2═R3═H, R=3,5-difluorophenyl,Ar=4-(4-methyl-piperazin-1-yl)-2-((R)-2-methoxy-1-methyl-ethylamino)-phenyl]cpd. 32

1H-NMR (400 MHz), δ (ppm, DMSO-d6): 1.14 (d, J=6.34 Hz, 3H) 2.23 (s, 3H)2.41-2.47 (m, 4H) 3.24-3.31 (m, 4H) 3.27 (s, 3H) 3.32-3.40 (m, 2H)3.74-3.83 (m, 1H) 4.05 (s, 2H) 6.13 (d, J=2.19 Hz, 1H) 6.24 (dd, J=9.02,2.20 Hz, 1H) 6.94-7.04 (m, 3H) 7.25 (dd, J=8.66, 1.59 Hz, 1H) 7.41 (d,J=8.54 Hz, 1H) 7.49 (s, 1H) 7.78 (d, J=9.02 Hz, 1H) 8.20 (d, J=7.68 Hz,1H) 10.04 (s, 1H) 12.63 (s, 1H)

N-[5-(3,5-Difluoro-benzyl)-1H-indazol-3-yl]-2-(2-methoxy-ethylamino)-4-(4-methyl-piperazin-1-yl)-benzamide[(I_(A)), R1═R2═R3═H, R=3,5-difluorophenyl,Ar=4-(4-methyl-piperazin-1-yl)-2-(2-methoxy-ethylamino)-phenyl] cpd. 26

1H-NMR (400 MHz), δ (ppm, DMSO-d6): 2.25 (s, 3H) 2.44-2.49 (m, 4H) 3.26(s, 3H) 3.27-3.31 (m, 6H) 3.54 (t, J=5.37 Hz, 2H) 4.05 (s, 2H) 6.09 (d,J=1.95 Hz, 1H) 6.25 (dd, J=8.96, 2.01 Hz, 1H) 6.94-7.00 (m, 2H)6.99-7.05 (m, 1H) 7.24 (dd, J=8.60, 1.52 Hz, 1H) 7.41 (d, J=8.66 Hz, 1H)7.51 (s, 1H) 7.79 (d, J=9.15 Hz, 1H) 8.23 (t, J=5.12 Hz, 1H) 10.06 (s,1H) 12.63 (s, 1H)

N-[5-(3,5-Difluoro-benzyl)-1H-indazol-3-yl]-4-[(3-dimethylamino-propyl)-methyl-amino]-2-nitro-benzamide[(I_(A)), R1═R2═R3═H, R=3,5-difluorophenyl,Ar=4-[(3-dimethylamino-propyl)-methyl-amino]-2-nitro-phenyl] cpd. 59

1H-NMR (400 MHz), δ (ppm, DMSO-d6): 1.68 (m, 2H) 2.15 (m, 6H) 2.25 (t,J=6.58 Hz, 2H) 3.02 (s, 3H) 3.48 (t, J=7.07 Hz, 2H) 4.05 (s, 2H)6.93-7.05 (m, 4H) 7.19 (d, J=2.44 Hz, 1H) 7.26 (dd, J=8.54, 1.46 Hz, 1H)7.42 (d, J=8.54 Hz, 1H) 7.62 (s, 1H) 7.68 (bs, 1H) 10.73 (s, 1H) 12.69(s, 1H)

2-Cyclohexylamino-N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-benzamide[(I_(A)), R1═R2═R3═H, R=3,5-difluorophenyl,Ar=4-(4-methyl-piperazin-1-yl)-2-cyclohexylamino-phenyl] cpd. 18

1H-NMR (400 MHz), δ (ppm, DMSO-d6): 12.61 (s, 1H) 10.04 (s, 1H) 8.26 (d,1H) 7.77 (d, 1H) 7.48 (s, 1H) 7.40 (d, 1H) 7.25 (dd, 1H) 6.90-7.00 (m,3H) 6.21 (dd, 1H) 6.08 (d, 1H) 4.03 (s, 2H) 3.45 (m, 1H) 3.25 (m, 4H)2.45 (bs, 4H) 2.24 (s, 3H) 1.88-1.23 (m, 10H)

N-{5-[1-(3,5-Difluoro-phenyl)ethyl]-1H-indazol-3-yl}-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide[(ID), R1═R2═R3═R″═H, R=3,5-difluorophenyl, R′=methyl,Ar=4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-phenyl]cpd. 75

1H-NMR (400 MHz), δ (ppm, DMSO-d6): 1.29-1.43 (m, 2H) 1.60 (d, J=7.19Hz, 3H) 1.89-1.99 (m, 2H) 2.29 (br. s., 3H) 2.45-2.57 (m, 4H) 3.22-3.38(m, 4H) 3.45-3.55 (m, 2H) 3.64-3.76 (m, 1H) 3.78-3.85 (m, 2H) 4.31 (q,J=7.40 Hz, 1H) 6.15 (d, J=1.95 Hz, 1H) 6.25 (dd, J=8.90, 2.19 Hz, 1H)6.94-7.06 (m, 3H) 7.28 (dd, J=8.78, 1.59 Hz, 1H) 7.40 (d, J=8.54 Hz, 1H)7.52 (s, 1H) 7.81 (d, J=9.15 Hz, 1H) 8.32 (d, J=7.68 Hz, 1H) 10.09 (s,1H) 12.62 (s, 1H)

Single enantiomers have been obtained by preparative chiral-HPLC byusing Daicel Chiralpak AD 250×20 mm 10 μm as column system andhexane/2-propanol 40:60 as eluant.

N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-2-[(1-methoxy-2-methylpropan-2-yl)amino]-4-(4-methylpiperazin-1-yl)benzamide[(I_(A)), R1═R2═R3═H, R=3,5-difluorophenyl,Ar=4-(4-methyl-piperazin-1-yl)-2-[(1-methoxy-2-methylpropan-2-yl)amino]-phenyl]cpd. 34

1H-NMR (400 MHz), δ (ppm, DMSO-d6): 1.31 (s, 6H) 2.27 (br. s., 3H) 2.50(m, 4H) 3.26 (m, 7H) 3.35 (s, 2H) 4.05 (s, 2H) 6.27 (dd, J=9.02, 2.32Hz, 1H) 6.31 (d, J=2.32 Hz, 1H) 6.93-7.05 (m, 3H) 7.25 (dd, J=8.60, 1.52Hz, 1H) 7.41 (d, J=8.54 Hz, 1H) 7.51-7.53 (m, 1H) 7.76 (d, J=8.90 Hz,1H) 8.26 (s, 1H) 10.14 (s, 1H) 12.63 (s, 1H)

N-[5-(3,5-Difluoro-benzyl)-1H-indazol-3-yl]-2-(2-methoxy-1-methoxymethyl-ethylamino)-4-(4-methyl-piperazin-1-yl)-benzamide[(I_(A)), R1═R2═R3═H, R=3,5-difluorophenyl,Ar=4-(4-methyl-piperazin-1-yl)-2-(2-methoxy-1-methoxymethyl-ethylamino)-phenyl]cpd. 16

1H-NMR (400 MHz), δ (ppm, DMSO-d6): 2.42 (br. s., 3H) 2.70 (br. s., 4H)3.26 (s, 6H) 3.30 (m, 4H) 3.41 (d, J=5.00 Hz, 4H) 3.85 (m, J=8.17, 5.00,5.00, 5.00, 5.00 Hz, 1H) 4.04 (s, 2H) 6.20 (d, J=1.95 Hz, 1H) 6.26 (dd,J=8.96, 2.01 Hz, 1H) 6.94-7.04 (m, 3H) 7.24 (dd, J=8.66, 1.46 Hz, 1H)7.41 (d, J=8.54 Hz, 1H) 7.48 (br. s., 1H) 7.79 (d, J=9.02 Hz, 1H) 8.32(d, J=8.29 Hz, 1H) 10.06 (s, 1H) 12.64 (s, 1H)

2-Benzylamino-N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-benzamide[(I_(A)), R1═R2═R3═H, R=3,5-difluorophenyl,Ar=4-(4-methyl-piperazin-1-yl)-2-benzylamino-phenyl] cpd. 24

1H-NMR (400 MHz), δ (ppm, DMSO-d6): 2.22 (s, 3H) 2.41 (br. s., 4H)3.19-3.24 (m, 4H) 4.04 (s, 2H) 4.39 (d, J=5.49 Hz, 2H) 6.09 (d, J=2.19Hz, 1H) 6.26 (dd, J=9.02, 2.32 Hz, 1H) 6.92-6.98 (m, 2H) 6.98-7.04 (m,1H) 7.21-7.27 (m, 2H) 7.30-7.36 (m, 2H) 7.36-7.39 (m, 2H) 7.40 (d,J=9.02 Hz, 1H) 7.51 (s, 1H) 7.81 (d, J=9.02 Hz, 1H) 8.60 (t, J=5.55 Hz,1H) 10.11 (s, 1H) 12.63 (s, 1H)

N-[5-(3,5-Difluoro-benzyl)-1H-indazol-3-yl]-2-(2-fluoro-ethylamino)-4-(4-methyl-piperazin-1-yl)-benzamide[(I_(A)), R1═R2═R3═H, R=3,5-difluorophenyl,Ar=4-(4-methyl-piperazin-1-yl)-2-(2-fluoro-ethylamino)-phenyl] cpd. 38

1H-NMR (400 MHz), δ (ppm, DMSO-d6): 2.24 (s, 3H) 2.43-2.48 (m, 4H)3.26-3.31 (m, 4H) 3.49 (dq, J=27.68, 5.12 Hz, 2H) 4.04 (s, 2H) 4.60 (dt,J=47.68, 4.76 Hz, 2H) 6.12 (d, J=2.23 Hz, 1H) 6.28 (dd, J=8.99, 2.23 Hz,1H) 6.94-7.00 (m, 2H) 6.99-7.04 (m, 1H) 7.24 (dd, J=8.57, 1.52 Hz, 1H)7.41 (d, J=8.57 Hz, 1H) 7.51 (s, 1H) 7.81 (d, J=8.99 Hz, 1H) 8.37 (t,J=5.43 Hz, 1H) 10.11 (s, 1H) 12.63 (s, 1H)

N-[5-(3,5-Difluoro-benzyl)-1H-indazol-3-yl]-2-(2-fluoro-propylamino)-4-(4-methyl-piperazin-1-yl)-benzamide[(I_(A)), R1═R2═R3═H, R=3,5-difluorophenyl,Ar=4-(4-methyl-piperazin-1-yl)-2-(2-fluoro-propylamino)-phenyl] cpd. 40

1H-NMR (400 MHz), δ (ppm, DMSO-d6): 1.86-2.04 (m, 2H) 2.26 (br. s., 3H)2.48 (br. s., 4H) 3.21-3.37 (m, 6H) 4.04 (s, 2H) 4.44-4.66 (dt, J=47.43,5.73 Hz, 2H) 6.09 (d, J=1.95 Hz, 1H) 6.26 (dd, J=9.02, 2.20 Hz, 1H)6.94-7.05 (m, 3H) 7.25 (dd, J=8.60, 1.40 Hz, 1H) 7.41 (d, J=8.66 Hz, 1H)7.50 (d, J=1.71 Hz, 1H) 7.81 (d, J=9.02 Hz, 1H) 8.22 (t, J=5.24 Hz, 1H)10.09 (s, 1H) 12.63 (s, 1H)

N-[5-(3,5-Difluoro-benzyl)-1H-indazol-3-yl]-4-[(3-dimethylamino-propyl)-methyl-amino]-2-(tetrahydro-pyran-4-ylamino)-benzamide[(I_(A)), R1═R2═R3═H, R=3,5-difluorophenyl,Ar=4-[(3-dimethylamino-propyl)-methyl-amino]-2-(tetrahydro-pyran-4-ylamino)-phenyl]cpd. 55

1H-NMR (400 MHz), δ (ppm, DMSO-d6): 1.32-1.44 (m, 2H) 1.67 (quin, J=6.98Hz, 2H) 1.93-1.98 (m, 2H) 2.17 (s, 6H) 2.26 (t, J=6.65 Hz, 2H) 2.96 (s,3H) 3.36-3.43 (m, 2H) 3.44-3.53 (m, 2H) 3.58-3.69 (m, 1H) 3.79-3.87 (m,2H) 4.05 (s, 2H) 5.87 (d, J=2.19 Hz, 1H) 6.04 (dd, J=9.02, 2.32 Hz, 1H)6.96-7.05 (m, 3H) 7.25 (dd, J=8.60, 1.52 Hz, 1H) 7.41 (d, J=8.54 Hz, 1H)7.49 (s, 1H) 7.77 (d, J=9.15 Hz, 1H) 8.35 (d, J=7.32 Hz, 1H) 9.96 (s,1H) 12.60 (s, 1H)

N-[5-(3,5-Difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-phenylamino-benzamide[(I_(A)) R1═R2═R3═H, R=3,5-difluorophenyl,Ar=4-(4-methyl-piperazin-1-yl)-2-phenylamino-phenyl] cpd. 42

1H-NMR (400 MHz), δ (ppm, DMSO-d6): 2.24 (s, 3H) 2.46 (br. s., 4H) 3.22(br. s., 4H) 4.05 (s, 2H) 6.53 (dd, J=9.02, 2.19 Hz, 1H) 6.74 (d, J=2.32Hz, 1H) 6.95-7.02 (m, 4H) 7.19 (d, J=7.56 Hz, 2H) 7.25 (dd, J=8.66, 1.46Hz, 1H) 7.29-7.35 (m, 2H) 7.40-7.44 (m, 1H) 7.55 (s, 1H) 7.91 (d, J=9.15Hz, 1H) 10.03 (s, 1H) 10.39 (s, 1H) 12.69 (s, 1H)

N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methy-1,4-diazepan-1-yl)-2-(tetrabydro-2H-pyran-4-ylamino)benzamide[(I_(A)), R1═R2═R3═H, R=3,5-difluorophenyl, Ar=4-(4-methyl-1,4diazepan-1-yl)-2-(tetrahydro-pyran-4-ylamino)-phenyl] cpd. 89

1H-NMR (400 MHz), δ (ppm, DMSO-d6): 1.31-1.42 (m, 2H) 1.83-1.98 (m, 4H)2.28 (s, 3H) 2.44-2.49 (m, 2H) 2.63 (d, J=4.51 Hz, 2H) 3.44-3.59 (m, 6H)3.65 (d, J=11.46 Hz, 1H) 3.78-3.85 (m, 2H) 4.04 (s, 2H) 5.87 (d, J=2.32Hz, 1H) 6.05 (dd, J=9.08, 2.26 Hz, 1H) 6.96-7.04 (m, 3H) 7.25 (dd,J=8.59, 1.52 Hz, 1H) 7.41 (d, J=8.53 Hz, 1H) 7.49 (s, 1H) 7.77 (d,J=9.14 Hz, 1H) 8.36 (d, J=7.68 Hz, 1H) 9.96 (s, 1H) 12.60 (s, 1H)

N-[5-(3,5-Difluoro-benzyl)-1H-indazol-3-yl]-4-[(2-dimethylamino-ethyl)-methyl-amino]-2-(tetrahydro-pyran-4-ylamino)-benzamide[(I_(A)), R1═R2═R3═H, R=3,5-difluorophenyl,Ar=4-[(2-dimethylamino-ethyl)-methyl-amino]-2-(tetrahydro-pyran-4-ylamino)-phenyl]cpd. 90

1H-NMR (400 MHz), δ (ppm, DMSO-d6): 1.32-1.43 (m, 2H) 1.96 (d, 1H)2.19-2.22 (m, 6H) 2.40 (t, J=7.19 Hz, 2H) 2.98 (s, 3H) 3.41-3.51 (m, 4H)3.56-3.65 (m, 1H) 3.80-3.87 (m, 2H) 4.04 (s, 2H) 5.87 (d, J=2.32 Hz, 1H)6.02 (dd, J=9.08, 2.38 Hz, 1H) 6.96-7.04 (m, 3H) 7.25 (dd, J=8.59, 1.52Hz, 1H) 7.41 (d, J=8.53 Hz, 1H) 7.49 (s, 1H) 7.78 (d, J=9.14 Hz, 1H)8.35 (d, J=7.31 Hz, 1H) 9.97 (s, 1H) 12.60 (s, 1H)

N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-[4-(dimethylamino)piperidin-1-yl]-2-(tetrahydro-2H-pyran-4-ylamino)benzamide[(I_(A)), R1═R2═R3═H, R=3,5-difluorophenyl,Ar=4-[4-(dimethylamino)piperidin-1-yl]-2-(tetrahydro-pyran-4-ylamino)-phenyl]cpd. 91

1H-NMR (400 MHz), δ (ppm, DMSO-d6): 1.43 (m, 4H) 1.82 (d, J=12.32 Hz,2H) 1.93 (dq, J=12.74, 2.77 Hz, 2H) 2.20 (s, 6H) 2.29 (m, 1H) 2.78 (td,J=12.38, 2.19 Hz, 2H) 3.49 (ddd, J=11.86, 9.91, 2.26 Hz, 2H) 3.62-3.72(m, 1H) 3.81 (dt, J=11.74, 4.07 Hz, 2H) 3.87 (d, J=12.56 Hz, 2H) 4.04(s, 2H) 6.12 (d, J=2.19 Hz, 1H) 6.23 (dd, J=8.96, 2.26 Hz, 1H) 6.99 (m,3H) 7.25 (dd, J=8.60, 1.52 Hz, 1H) 7.40 (d, J=8.54 Hz, 1H) 7.48 (br. s.,1H) 7.78 (d, J=9.15 Hz, 1H) 8.28 (d, J=7.56 Hz, 1H) 10.05 (s, 1H) 12.61(s, 1H)

N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-[(2S)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]-2-(tetrahydro-2H-pyran-1-ylamino)benzamide[(I_(A)), R1═R2═R3═H, R=3,5-difluorophenyl,Ar=4-[(2S)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]-2-(tetrahydro-pyran-4-ylamino)-phenyl]cpd. 92

1H-NMR (400 MHz), δ (ppm, DMSO-d6): 1.36 (m, 2H) 1.72 (m, 4H) 1.99 (m,6H) 2.43 (m, 3H) 2.63 (m, 2H) 3.16 (m, 2H) 3.39-3.47 (m, 3H) 3.58 (br.s., 1H) 3.82-3.90 (m, 2H) 3.90 (br. s., 1H) 4.04 (s, 2H) 5.82 (d, J=1.59Hz, 1H) 5.90 (dd, J=8.90, 2.07 Hz, 1H) 6.98 (m, 3H) 7.24 (dd, J=8.60,1.52 Hz, 1H) 7.40 (d, J=8.90 Hz, 1H) 7.48 (br. s., 1H) 7.77 (d, J=9.02Hz, 1H) 8.36 (d, J=7.32 Hz, 1H) 9.95 (s, 1H) 12.60 (s, 1H)

N-[5-(3,5-difluorobenzyl)-1H-Indazol-3-yl]-3-(4-methylpiperazin-1-yl)benzamide[(I_(A)), R1═R2═R3═H, R=3,5-difluorophenyl,Ar=3-(4-methylpiperazin-1-yl)phenyl] cpd. 93

1H-NMR (400 MHz), δ (ppm, DMSO-d6): 2.26 (s, 3H) 2.47-2.54 (m, 4H)3.22-3.27 (m, 4H) 4.06 (s, 2H) 6.92-6.99 (m, 2H) 6.99-7.06 (m, 1H)7.15-7.20 (m, 1H) 7.26 (dd, J=8.66, 1.59 Hz, 1H) 7.36 (t, J=7.93 Hz, 1H)7.42-7.45 (m, 1H) 7.47 (d, J=7.80 Hz, 1H) 7.60-7.63 (m, 2H) 10.65 (s,1H) 12.73 (s, 1H)

N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide[(I_(A)), R1═R2═R3═H, R=3,5-difluorophenyl,Ar=4-(piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)phenyl] cpd. 98

1H-NMR (400 MHz), δ (ppm, DMSO-d6): 1.30-1.41 (m, 2H) 1.88-2.01 (m, 2H)2.81-2.88 (m, 4H) 3.17-3.22 (m, 4H) 3.45-3.54 (m, 2H) 3.62-3.73 (m, 1H)3.78-3.85 (m, 2H) 4.05 (s, 2H) 6.12 (d, J=2.19 Hz, 1H) 6.23 (dd, J=8.96,2.26 Hz, 1H) 6.94-7.04 (m, 3H) 7.26 (dd, J=8.65, 1.58 Hz, 1H) 7.39-7.43(m, 1H) 7.49 (s, 1H) 7.80 (d, J=9.02 Hz, 1H) 8.29 (d, J=7.68 Hz, 1H)10.07 (s, 1H) 12.63 (s, 1H)

N-[5-(3,5-difluorobenzyl)-1H-Indazol-3-yl]-4-(4-methylpiperazin-1-yl)-2-{[cis-4-(trifluoromethyl)cyclohexyl]amino}benzamide[(I_(A)), R1═R2═R3═H, R=3,5-difluorophenyl,Ar=4-(4-methyl-piperazin-1-yl)-2-{[cis-4-(trifluoromethyl)cyclohexyl]amino}phenyl]cpd. 99

1H-NMR (400 MHz), δ (ppm, DMSO-d6): 1.39-1.53 (m, 2H) 1.58-1.73 (m, 4H)1.84-1.91 (m, 2H) 2.25 (s, 3H) 2.28-2.40 (m, 1H) 2.47 (br. s., 4H)3.25-3.33 (m, 4H) 3.82-3.90 (m, 1H) 4.01 (s, 2H) 6.10 (d, J=1.95 Hz, 1H)6.24 (dd, J=9.15, 2.19 Hz, 1H) 6.90-6.96 (m, 2H) 6.96-7.03 (m, 1H) 7.24(dd, J=8.60, 1.52 Hz, 1H) 7.42 (d, J=8.54 Hz, 1H) 7.52 (s, 1H) 7.83 (d,J=9.02 Hz, 1H) 8.69 (d, J=7.80 Hz, 1H) 10.10 (s, 1H) 12.65 (s, 1H)

N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methylpiperazin-1-yl)-2-{[trans-4-(trifluoromethyl)cyclohexyl]amino}benzamide[(I), R1═R2═R3═H, R=3,5-difluorophenyl,Ar=4-(4-methyl-piperazin-1-yl)-2-{[trans-4-(trifluoromethyl)cyclohexyl]amino}phenyl]cpd. 100

1H-NMR (400 MHz), δ (ppm, DMSO-d6): 1.10-1.23 (m, 2H) 1.44-1.57 (m, 2H)1.86-1.94 (m, 2H) 2.06-2.15 (m, 2H) 2.25 (s, 3H) 2.29-2.34 (m, 1H) 2.46(br. s., 4H) 3.24-3.31 (m, 4H) 3.39-3.51 (m, 1H) 4.05 (s, 2H) 6.15 (d,J=2.07 Hz, 1H) 6.23 (dd, J=8.90, 2.07 Hz, 1H) 6.95-7.00 (m, 2H)7.00-7.06 (m, 1H) 7.25 (dd, J=8.60, 1.52 Hz, 1H) 7.41 (d, J=8.54 Hz, 1H)7.48 (s, 1H) 7.78 (d, J=9.02 Hz, 1H) 8.14 (d, J=8.05 Hz, 1H) 10.05 (s,1H) 12.62 (s, 1H)

N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-2-fluoro-4-(4-methylpiperazin-1-yl)benzamide[(I_(A)), R1═R2═R3═H, R=3,5-difluorophenyl,Ar=4-(4-methyl-piperazin-1-yl)-2-fluoro-phenyl] cpd. 101

1H-NMR (400 MHz), δ (ppm, DMSO-d6): 2.26 (s, 3H) 2.45-2.50 (m, 4H)3.29-3.36 (m, 4H) 4.06 (s, 2H) 6.78-6.89 (m, 2H) 6.94-6.98 (m, 2H)6.98-7.06 (m, 1H) 7.25 (dd, J=8.54, 1.59 Hz, 1H) 7.42 (d, J=8.66 Hz, 1H)7.64 (s, 1H) 7.68 (t, J=8.90 Hz, 1H) 10.08 (d, J=3.41 Hz, 1H) 12.68 (s,1H)

N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-2-[(1-methylpiperidin-4-yl)amino]benzamide[(I_(A)), R1═R2═R3═H, R=3,5-difluorophenyl,Ar=2-[(1-methylpiperidin-4-yl)amino]-phenyl] cpd. 110

1H-NMR (400 MHz), δ (ppm, DMSO-d6): 1.35-1.49 (m, H) 1.94 (d, H) 2.20(br. s., 5H) 2.60-2.73 (m, 2H) 3.38-3.47 (m, 1H) 4.05 (s, 2H) 6.58-6.64(m, 1H) 6.80 (d, J=8.29 Hz, 1H) 6.95-7.00 (m, 2H) 7.00-7.05 (m, 1H) 7.27(dd, J=8.65, 1.58 Hz, 1H) 7.32-7.37 (m, 1H) 7.44 (d, J=8.53 Hz, 1H) 7.53(s, 1H) 7.85-7.88 (m, 1H) 7.89 (dd, J=8.05, 1.34 Hz, 1H) 10.44 (s, 1H)12.72 (s, 1H)

N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-2-[(1-methylpiperidin-1-yl)amino]4-(morpholin-4-yl)benzamide[(I_(A)), R1═R2═R3═H, R=3,5-difluorophenyl,Ar=4-(morpholin-4-yl)-2-[(1-methylpiperidin-4-yl)amino]-phenyl] cpd. 111

1H-NMR (400 MHz), δ (ppm, DMSO-d6): 1.38-1.50 (m, 2H) 1.91-2.01 (m, 2H)2.27 (m, 5H) 2.72 (m, 2H) 3.20-3.26 (m, 4H) 3.50 (br. s., 1H) 3.72-3.78(m, 4H) 4.05 (s, 2H) 6.11 (d, J=2.19 Hz, 1H) 6.25 (dd, J=9.08, 2.13 Hz,1H) 6.92-7.08 (m, 3H) 7.26 (dd, J=8.59, 1.52 Hz, 1H) 7.42 (d, J=8.53 Hz,1H) 7.50 (s, 1H) 7.82 (d, J=9.02 Hz, 1H) 8.28 (d, J=7.31 Hz, 1H) 10.10(s, 1H) 12.64 (s, 1H)

N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-2-methoxy-4-(4-methylpiperazin-1-yl)benzamide[(I_(A)), R1═R2═R3═H, R=3,5-difluorophenyl,Ar=4-(4-methyl-piperazin-1-yl)-2-methoxy-amino}phenyl] cpd. 112

1H-NMR (400 MHz), δ (ppm, DMSO-d6): 2.25 (s, 3H) 2.47 (br. s., 4H)3.33-3.38 (m, 4H) 4.02 (s, 3H) 4.06 (s, 2H) 6.63 (d, J=1.95 Hz, 1H) 6.67(dd, J=8.96, 2.13 Hz, 1H) 6.96 (dd, J=8.72, 2.13 Hz, 2H) 6.99-7.05 (m,1H) 7.24 (dd, J=8.66, 1.59 Hz, 1H) 7.40 (d, J=8.66 Hz, 1H) 7.76 (s, 1H)7.88 (d, J=8.78 Hz, 1H) 9.99 (s, 1H) 12.65 (s, 1H)

N-[5-(2,5-Difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide[(I), R1═R2═R3═H, R=2,5-difluorophenyl,Ar=4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-phenyl]cpd. 10

1H-NMR (400 MHz), δ (ppm, DMSO-d6): 1.29-1.42 (m, 2H) 1.90-1.98 (m, 2H)2.27 (br. s., 3H) 2.49 (br. s., 4H) 3.24-3.32 (m, 4H) 3.45-3.56 (m, 2H)3.64-3.74 (m, 1H) 3.82 (ddd, J=11.80, 3.96, 3.75 Hz, 2H) 4.04 (s, 2H)6.14 (d, J=1.83 Hz, 1H) 6.24 (dd, J=8.90, 1.95 Hz, 1H) 7.04-7.12 (m, 1H)7.15-7.23 (m, 2H) 7.24-7.27 (m, 1H) 7.41 (d, J=8.66 Hz, 1H) 7.46 (s, 1H)7.80 (d, J=9.02 Hz, 1H) 8.30 (d, J=7.68 Hz, 1H) 10.08 (s, 1H) 12.63 (s,1H)

N-[5-(2-methyl-5-fluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide[(I_(A)), R1═R2═R3═H, R=2-methyl-5-fluorophenyl,Ar=4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-phenyl]cpd. 135

1H-NMR (400 MHz), δ (ppm, DMSO-d6): 1.29-1.41 (m, 2H) 1.94 (dd, J=13.35,2.86 Hz, 2H) 2.22 (s, 3H) 2.25 (s, 3H) 2.46 (br. s., 4H) 3.24-3.30 (m,4H) 3.46-3.54 (m, 2H) 3.63-3.73 (m, 1H) 3.78-3.86 (m, 2H) 4.03 (s, 2H)6.13 (d, J=1.95 Hz, 1H) 6.23 (dd, J=9.02, 2.07 Hz, 1H) 6.89-6.98 (m, 2H)7.14-7.21 (m, 2H) 7.38 (s, 1H) 7.41 (d, J=8.65 Hz, 1H) 7.79 (d, J=9.02Hz, 1H) 8.31 (d, J=7.80 Hz, 1H) 10.07 (s, 1H) 12.61 (s, 1H)

N-[5-(2-fluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide[(I_(A)), R1═R2═R3═H, R=2-fluorophenyl,Ar=4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-phenyl]cpd. 9

1H-NMR (400 MHz), δ (ppm, DMSO-d6): 1.29-1.42 (m, 2H) 1.89-1.98 (m, 2H)2.24 (s, 3H) 2.45 (br. s., 4H) 3.24-3.30 (m, 4H) 3.47-3.55 (m, 2H)3.64-3.74 (m, 1H) 3.77-3.87 (m, 2H) 4.04 (s, 2H) 6.14 (d, J=2.19 Hz, 1H)6.24 (dd, J=8.96, 2.26 Hz, 1H) 6.95-7.02 (m, 1H) 7.04-7.09 (m, 1H) 7.10(d, J=7.56 Hz, 1H) 7.24 (dd, J=8.66, 1.46 Hz, 1H) 7.31 (td, J=7.80, 6.34Hz, 1H) 7.40 (d, J=8.53 Hz, 1H) 7.46 (s, 1H) 7.79 (d, J=9.02 Hz, 1H)8.28 (d, J=7.80 Hz, 1H) 10.07 (s, 1H) 12.61 (s, 1H)

4-(4-methylpiperazin-1-yl)-N-[5-(pyridin-3-ylmethyl)-1H-indazol-3-yl]-2-(tetrahydro-2H-pyran-4-ylamino)benzamide[(I_(A)), R1═R2═R3═H, R=pyridin-3-yl,Ar=4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-phenyl]cpd. 136

1H-NMR (400 MHz), δ (ppm, DMSO-d6): 1.30-1.42 (m, 2H) 1.95 (d, 2H) 2.26(s, 3H) 2.47 (br. s., 4H) 3.25-3.30 (m, 4H) 3.47-3.54 (m, 2H) 3.64-3.74(m, 1H) 3.79-3.86 (m, 2H) 4.05 (s, 2H) 6.14 (d, J=2.07 Hz, 1H) 6.24 (dd,J=8.90, 2.19 Hz, 1H) 7.24 (dd, J=8.60, 1.52 Hz, 1H) 7.29 (ddd, J=7.80,4.76, 0.73 Hz, 1H) 7.41 (d, J=8.90 Hz, 1H) 7.47 (s, 1H) 7.63 (dt,J=7.87, 1.92 Hz, 1H) 7.79 (d, J=9.15 Hz, 1H) 8.27 (d, J=7.80 Hz, 1H)8.39 (dd, J=4.76, 1.59 Hz, 1H) 8.52 (d, J=1.71 Hz, 1H) 10.07 (s, 1H)12.62 (s, 1H)

N-[5-benzyl-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide[(I_(A)), R1═R2═R3═H, R=phenyl,Ar=4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-phenyl]cpd. 137

1H-NMR (400 MHz), δ (ppm, DMSO-d6): 1.31-1.42 (m, 2H) 1.90-1.99 (m, 2H)2.24 (s, 3H) 2.42-2.47 (m, 4H) 3.24-3.31 (m, 4H) 3.46-3.55 (m, 2H)3.64-3.76 (m, 1H) 3.78-3.87 (m, 2H) 4.01 (s, 2H) 6.14 (d, J=2.07 Hz, 1H)6.24 (dd, J=8.96, 2.26 Hz, 1H) 7.17-7.27 (m, 6H) 7.38 (d, J=8.90 Hz, 1H)7.44 (s, 1H) 7.79 (d, J=9.02 Hz, 1H) 8.28 (d, J=7.68 Hz, 1H) 10.05 (s,1H) 12.59 (s, 1H).

Example 3 Step rN-[5-(3,5-Difluoro-benzyl)-1H-indazol-3-yl]-2,2,2-trifluoro-acetamide[(XXIV_(A)), R1═R2═R3═H, R=3,5-difluorophenyl, PG₁=trifluoroacethyl]

To a suspension of 5-(3,5-difluoro-benzyl)-1H-indazol-3-ylamine (0.5 g,1.93 mmol) in anhydrous dichloromethane (20 mL), under vigorous stirringand cooled to 0° C., trifluoroacetic anhydride was added dropwise andthe dense slurry was stirred for 3.5 hours. The reaction mixture waspoured into 3% NaHCO₃ solution and extracted with dichloromethane. Theorganic layer was washed with brine, dried over Na₂SO₄ and concentratedto yield a crude white solid that was directly used in the next step.

ESI (+) MS m/z 356 (100, MH⁺); HRMS (ESI) calcd forC₁₆H₁₀F₅N₃O+H⁺356.0817 found 356.0820.

Step sN-[5-(3,5-Difluoro-benzyl)-1-trityl-1H-indazol-3-yl]-2,2,2-trifluoro-acetamide[(XXV_(A)), R1═R2═R3═H, R=3,5-difluorophenyl, PG-triphenylmethyl,PG₁=trifluoroacethyl]

CrudeN-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-2,2,2-trifluoro-acetamidewas suspended in dichloromethane (25 mL) and treated with tritylchloride (0.72 g, 2.58 mmol) under stirring. The suspension was cooledto 0° C. and neat 1,8-diazabicyclo[5.4.0]undec-7-ene (0.42 mL, 2.78mmol) was added, producing immediate solubilization. After stirring at0° C. for 3 hours the reaction mixture was poured into 50 mL of icecontaining 1N HCl (5 mL) and extracted with dichloromethane. The organiclayer was washed with NaHCO₃, brine, dried and concentrated to a crudematerial that was purified by flash chromatography (eluant: DCM). Thedesired product was obtained as a white solid (450 mg, yield 40% overtwo steps)

1H-NMR (400 MHz), δ (ppm, DMSO-d6): 3.98 (s, 2H) 6.34 (d, J=8.78 Hz, 1H)6.93-7.07 (m, 4H) 7.16-7.20 (m, 6H) 7.25-7.39 (m, 9H) 7.52 (s, 1H) 11.99(s, 1H)

Step t 5-(3,5-Difluoro-benzyl)-1-trityl-1H-indazol-3-ylamine[(XXVI_(A)), R1═R2═R3═H, R=3,5-difluorophenyl, PG=triphenylmethyl]

N-[5-(3,5-Difluoro-benzyl)-1-trityl-1H-indazol-3-yl]-2,2,2-trifluoro-acetamide(450 mg, 0.75 mmol) was dissolved in methanol (6 mL) and triethylamine(1.5 mL) and the solution was refluxed for 3 hours. The solvents wereremoved under reduced pressure and the residue was purified by flashchromatography (eluant: DCM). Title compound was isolated as white foam(300 mg, yield 80%).

1H-NMR (400 MHz), δ (ppm, DMSO-d6): 3.91 (s, 2H) 5.53 (s, 2H) 6.24 (d,J=8.78 Hz, 1H) 6.87-6.93 (m, 3H) 6.97-7.07 (m, 1H) 7.17-7.23 (m, 3H)7.27 (t, J=7.50 Hz, 6H) 7.34 (d, J=1.59 Hz, 6H) 7.48 (s, 1H)

Step uN-[5-(3,5-Difluoro-benzyl)-1-trityl-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-nitro-benzamide[(XXII_(A)), R1═R2═R3═H, R=3,5-difluorophenyl,Ar=4-(4-methyl-piperazin-1-yl)-2-nitro-phenyl, PG=triphenylmethyl]

4-(4-Methyl-piperazin-1-yl)-2-nitro-benzoic acid (150 mg, 0.5 mmol) wassuspended in anhydrous dichloromethane (10 mL), a drop of DMF was added,followed by oxalyl chloride (0.2 mL, 2 mmol). After stirring at roomtemperature for 2 hours the mixture was thoroughly dried under reducedpressure to give the acyl chloride as a white powder. 120 mg of the acylchloride (0.4 mmol) were dissolved in anhydrous tetrahydrofuran (3 mL)and 5-(3,5-difluoro-benzyl)-1-trityl-1H-indazol-3-ylamine (200 mg, 0.4mmol) was added. The resulting solution was cooled to 0° C. understirring. After addition of diisopropyethylamine (0.2 mL, 1.2 mmol), thereaction mixture was stirred for 18 hours, while temperature wasgradually increasing from 0° C. to room temperature. After evaporationof the volatiles, the crude residue was purified by flash chromatography(eluant: DCM/MeOH 10:1). Title compound was isolated as a bright yellowsolid (200 mg, yield 67%).

1H-NMR (400 MHz), δ (ppm, DMSO-d6): 2.24 (s, 3H) 2.45 (br. s., 4H)3.31-3.39 (m, 4H) 3.96 (s, 2H) 6.29 (br. s., 1H) 6.98 (m, 4H) 7.29 (m,17H) 7.58 (s, 1H) 7.70 (br. s., 1H) 10.96 (br. s., 1H)

Step i″N-[5-(3,5-Difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-nitro-benzamidehydrochloride [(I_(A)), R1═R2═R3═H, R=3,5-difluorophenyl,Ar=4-(4-methyl-piperazin-1-yl)-2-nitro-phenyl] cpd. 6

To a solution ofN-[5-(3,5-difluoro-benzyl)-1-trityl-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-nitro-benzamide(28.5 mg, 0.04 mmol) in dioxane (1 mL), 4 M HCl in dioxane (0.1 mL) wasadded and the mixture was stirred at room temperature for 1 hour. Afterconcentration the residue was suspended in diethyl ether/MeOH 1:1,stirred for 20 min., filtered, washed with the same solvent mixture anddried. The desired product was obtained as hydrochloride derivative (19mg, 87%).

1H-NMR (400 MHz), δ (ppm, DMSO-d6): 2.85 (d, J=4.02 Hz, 3H) 3.08-3.31(m, 4H) 3.53 (d, J=11.71 Hz, 2H) 4.06 (s, 2H) 4.13 (d, J=13.17 Hz, 2H)6.91-6.99 (m, 2H) 6.99-7.08 (m, 1H) 7.26 (dd, J=8.54, 1.34 Hz, 1H) 7.37(d, J=6.95 Hz, 1H) 7.43 (d, J=8.66 Hz, 1H) 7.58 (br. s., 1H) 7.64 (s,1H) 7.78 (d, J=7.44 Hz, 1H) 10.39 (br. s., 1H) 10.91 (br. s., 1H) 12.74(br. s., 1H)

Operating in an analogous way, the following compound was obtained:

2-Amino-N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-benzamidehydrochloride [(I_(A)), R1═R2═R3═H, R=3,5-difluorophenyl,Ar=4-(4-methyl-piperazin-1-yl)-2-amino-phenyl] cpd. 8

1H-NMR (400 MHz), δ (ppm, DMSO-d6): 2.84 (d, J=4.39 Hz, 3H) 3.05-3.20(m, 4H) 3.44-3.53 (m, 2H) 3.85-3.94 (m, 2H) 4.05 (s, 2H) 6.30 (d, J=1.95Hz, 1H) 6.36 (dd, J=8.96, 2.13 Hz, 1H) 6.93-7.00 (m, 2H) 6.99-7.05 (m,1H) 7.24 (dd, J=8.66, 1.46 Hz, 1H) 7.41 (d, J=8.41 Hz, 1H) 7.53 (s, 1H)7.81 (d, J=9.02 Hz, 1H) 10.11 (br. s., 1H) 10.37 (br. s., 1H) 12.66 (br.s., 1H)

Example 4 Conversion 12-Amino-N-[5-(3,5-difluoro-benzyl)-1-trityl-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-benzamide[(XXII_(A)), R1═R2═R3═H, R=3,5-difluorophenyl,Ar=4-(4-methyl-piperazin-1-yl)-2-amino-phenyl, PG-triphenylmethyl]

A mixture ofN-[5-(3,5-difluoro-benzyl)-1-trityl-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-nitro-benzamide(170 mg, 0.236 mmol), 10% Pd—C (10 mg) and ammonium formate (25 mg, 0.4mmol) in methanol (5 mL) was stirred for 18 hours at room temperature.The catalyst was filtered off and the solution was concentrated. Theresidue was dissolved in dichloromethane, washed with aqueous solutionof NaHCO₃, dried and concentrated to yield title compound (145 mg, 87%).

ESI (+) MS m/z 243 (100, trityl⁺), 719 (16, MH⁺); HRMS (ESI) calcd forC₄₅H₄₀F₂N₆O+H⁺719.3304 found 719.3309.

Operating in an analogous way, the following compounds were obtained:

2-Amino-N-[5-(3-ethoxy-benzoyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-benzamide[(II), R1═R2═R3═H, R=3-ethoxyphenyl,Ar=4-(4-methyl-piperazin-1-yl)-2-amino-phenyl]

1H-NMR (400 MHz), δ (ppm, DMSO-d6): 1.33 (t, J=6.95 Hz, 3H) 2.22 (s, 3H)2.40-2.45 (m, 4H) 3.16-3.22 (m, 4H) 4.09 (q, J=6.95 Hz, 2H) 6.17 (d,J=2.44 Hz, 1H) 6.23 (dd, J=9.02, 2.44 Hz, 1H) 6.53 (s, 2H) 7.18 (ddd,J=8.23, 2.62, 0.85 Hz, 1H) 7.24 (dd, J=2.44, 1.46 Hz, 1H) 7.29 (dt,J=7.68, 1.10 Hz, 1H) 7.44 (t, J=7.93 Hz, 1H) 7.59 (dd, J=8.84, 0.55 Hz,1H) 7.71 (d, J=9.15 Hz, 1H) 7.83 (dd, J=8.78, 1.59 Hz, 1H) 8.20 (br. s.,1H) 10.30 (s, 1H) 13.05 (s, 1H)

2-Amino-N-[5-(3,5-difluoro-benzoyl)-1H-indazol-3-yl]4-(4-methyl-piperazin-1-yl)-benzamide[(II), R1═R2═R3═H, R=3,5-difluorophenyl,Ar=4-(4-methyl-piperazin-1-yl)-2-amino-phenyl]

1H-NMR (400 MHz), δ (ppm, DMSO-d6): 2.30 (br. s., 3H) 2.56 (m, 4H) 3.22(m, 4H) 6.18 (d, J=2.32 Hz, 1H) 6.24 (dd, J=9.08, 2.38 Hz, 1H) 6.57 (s,2H) 7.42 (m, 2H) 7.54 (tt, J=9.15, 2.38 Hz, 1H) 7.61 (dd, J=8.90, 0.61Hz, 1H) 7.73 (d, J=9.02 Hz, 1H) 7.83 (dd, J=8.84, 1.65 Hz, 1H) 8.26 (d,J=0.98 Hz, 1H) 10.36 (s, 1H) 13.11 (s, 1H)

Example 5 Conversion 2+step i″N-[5-(3,5-Difluoro-benzyl)-1H-indazol-3-yl]-2-methanesulfonylamino-4-(4-methyl-piperazin-1-yl)-benzamidehydrochloride [(I_(A)), R1═R2═R3═H, R=3,5-difluorophenyl,Ar=4-(4-methyl-piperazin-1-yl)-2-methanesulfonylamino-phenyl] cpd. 48

To a solution of2-amino-N-[5-(3,5-difluoro-benzyl)-1-trityl-1H-indazol-3-yl]4-(4-methyl-piperazin-1-yl)-benzamide(29 mg, 0.04 mmol) in anhydrous dichloromethane (2 mL) and dry pyridine(0.05 mL), methanesulfonyl chloride (14.7 mg, 0.01 mL, 0.13 mmol) wasadded and the reaction mixture was stirred at room temperature for 8hours. The mixture was poured into ice and was extracted withdichloromethane. The organic layer was washed with 0.1N HCl, then withwater, dried over anhydrous Na₂SO₄ and concentrated to yield a crudewhitish solid that was suspended in dioxane (1 mL). After adding 4M HClin dioxane (0.1 mL) the suspension was stirred overnight. Afterconcentration the residue was suspended in diethyl ether/MeOH 1:1,stirred for 20 min., filtered, washed with the same solvent mixture anddried. The desired product was obtained as the hydrochloride (15 mg,0.025 mmol, 63%).

1H-NMR (400 MHz), δ (ppm, DMSO-d6): 2.86 (d, J=4.27 Hz, 3H) 3.17 (s, 3H)3.14-3.27 (m, 4H) 3.55 (m, 2H) 4.02 (m, 2H) 4.06 (s, 2H) 6.92 (dd,J=9.02, 2.32 Hz, 1H) 6.97-7.03 (m, 3H) 7.05 (d, J=2.56 Hz, 1H) 7.28 (dd,J=8.66, 1.46 Hz, 1H) 7.45 (d, J=8.54 Hz, 1H) 7.55 (s, 1H) 8.12 (d,J=9.15 Hz, 1H) 10.56 (s, 1H) 10.76 (s, 1H) 11.42 (s, 1H) 12.84 (s, 1H)

Operating in an analogous way, the following compounds were obtained:

N-[2-{[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]carbamoyl}-5-(4-methylpiperazin-1-yl)phenyl]-1H-pyrrole-2-carboxamidehydrochloride [(I_(A)), R1═R2═R3═H, R=3,5-difluorophenyl,Ar=4-(4-methylpiperazin-1-yl)-2-(1H-pyrrole-2-carbamoyl)-phenyl] cpd. 44

1H-NMR (400 MHz), δ (ppm, DMSO-d6): 2.74 (br. s., 3H) 4.04 (s, 2H) 6.09(dt, J=3.60, 2.41 Hz, 1H) 6.65 (dt, J=3.87, 1.78 Hz, 1H) 6.82 (dd,J=9.02, 2.32 Hz, 1H) 6.97 (m, 4H) 7.28 (dd, J=8.66, 1.46 Hz, 1H) 7.46(d, J=8.66 Hz, 1H) 7.59 (br. s., 1H) 8.09 (d, J=9.15 Hz, 1H) 8.38 (d,J=2.44 Hz, 1H) 9.99 (br. s., 1H) 10.71 (s, 1H) 11.69 (br. s., 1H) 12.51(s, 1H) 12.82 (s, 1H)

Example 6 Conversion 42-Amino-N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-benzamide[(I_(A)), R1═R2═R3═H, R=3,5-difluorophenyl,Ar=4-(4-methyl-piperazin-1-yl)-2-amino-phenyl] cpd. 8

A mixture ofN-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-nitro-benzamide(3.21 g, 6.33 mmol), cyclohexene (20 mL), dioxane (200 mL) and 10% Pd/C(0.8 g) was stirred at 100° C. for 2 hours. The reaction mixture wasfiltered over a celite pad washing thoroughly with THF and MeOH. Afterevaporation of the organic phase, purification of the crude bychromatography over silica gel (DCM/MeOH 95/5) gave 2.51 g of titlecompound (83% yield).

1H-NMR (400 MHz), δ (ppm, DMSO-d6): 2.23 (s, 3H) 2.44 (br. s., 4H) 3.20(t, J=4.76 Hz, 4H) 4.04 (s, 2H) 6.18 (d, J=2.44 Hz, 1H) 6.24 (dd,J=8.96, 2.38 Hz, 1H) 6.53 (s, 2H) 6.97 (m, 3H) 7.22 (dd, J=8.66, 1.59Hz, 1H) 7.39 (d, J=8.66 Hz, 1H) 7.52 (br. s., 1H) 7.72 (d, J=9.02 Hz,1H) 10.01 (s, 1H) 12.60 (s, 1H)

Operating in an analogous way, the following compounds were obtained:

2-Amino-4-[(3-dimethylamino-propyl)-methyl-amino]-N-[5-(3-ethoxy-benzyl)-1H-indazol-3-yl]-benzamide[(I_(A)), R1═R2═R3═H, R=3-ethoxyphenyl,Ar=4-[(3-dimethylamino-propyl)-methyl-amino]-2-amino-phenyl] cpd. 54

1H-NMR (400 MHz), δ (ppm, DMSO-d6): 1.27 (t, J=6.95 Hz, 3H) 1.67 (d,J=7.19 Hz, 2H) 2.19 (s, 6H) 2.28 (t, J=6.04 Hz, 2H) 2.90 (s, 3H)3.24-3.40 (m, 2H) 3.96 (q, J=6.95 Hz, 2H) 3.95 (s, 2H) 5.94 (d, J=2.56Hz, 1H) 6.04 (dd, J=9.02, 2.56 Hz, 1H) 6.52 (s, 2H) 6.68-6.72 (m, 1H)6.76-6.79 (m, 1H) 6.77 (s, 1H) 7.13-7.17 (m, 1H) 7.18 (dd, J=8.60, 1.65Hz, 1H) 7.33-7.38 (m, 1H) 7.47 (s, 1H) 7.69 (d, J=9.02 Hz, 1H) 9.88 (s,1H) 12.53 (s, 1H)

2-amino-N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-{[(2S)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]carbonyl}benzamide

1H-NMR (400 MHz), δ (ppm, DMSO-d6): 3.29-3.48 (m, 2H) 4.06 (s, 2H) 4.29(br. s., 1H) 6.63 (br. s., 3H) 6.85 (br. s., 1H) 6.92-7.05 (m, 3H) 7.26(dd, J=8.66, 1.34 Hz, 1H) 7.43 (d, J=8.54 Hz, 1H) 7.57 (s, 1H) 7.85 (d,J=8.17 Hz, 1H) 10.46 (s, 1H) 12.72 (s, 1H)

2-amino-N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-{[(2R)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]carbonyl}benzamide

ESI(+) MS: m/z 559 (MH⁺).

2-amino-N¹-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-N⁴-[2-(dimethylamino)ethyl]-N⁴-methylbenzene-1,4-dicarboxamide

ESI(+) MS: m/z 507 (MH⁺).

2-amino-N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-{[4-(propan-2-yl)piperazin-1-yl]carbonyl}benzamide

1H-NMR (400 MHz), δ (ppm, DMSO-d6): 0.99 (d, J=6.46 Hz, 6H) 2.43 (m, 4H)2.70 (d, 1H) 3.58 (m, 4H) 4.06 (s, 2H) 6.54 (dd, J=8.05, 1.46 Hz, 1H)6.65 (s, 2H) 6.75 (d, J=1.46 Hz, 1H) 6.92-7.01 (m, 2H) 6.99-7.05 (in,1H) 7.26 (dd, J=8.59, 1.52 Hz, 1H) 7.43 (d, J=8.65 Hz, 1H) 7.57 (s, 1H)7.85 (d, J=8.17 Hz, 1H) 10.45 (s, 11H) 12.71 (s, 1H)

2-amino-N¹-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-N⁴-[2-(dimethylamino)ethyl]benzene-1,4-dicarbozamide

ESI(+) MS: m/z 493 (MH⁺).

2-amino-N-[5-(3,5-dfluorobenzyl)-1H-indazol-3-yl]-4-[(4-methylpiperazin-1-yl)carbonyl]benzamide

1H-NMR (400 MHz), δ (ppm, DMSO-d6): 4.06 (s, 2H) 6.60 (d, J=8.29 Hz, 1H)6.68 (s, 2H) 6.80 (d, J=1.46 Hz, 1H) 6.93-7.00 (m, 2N) 7.00-7.06 (m, 1H)7.26 (dd, J=8.53, 1.58 Hz, 1H) 7.44 (d, J=8.65 Hz, 1H) 7.55 (s, NH) 7.88(d, J=8.17 Hz, 1H) 10.48 (s, 1H) 12.73 (s, 1H)

2-amino-N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}benzamide

ESI(+) MS: m/z 533 (MH⁺).

2-amino-N¹-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-N⁴-(1-methylpiperidin-4-yl)benzene-1,4-dicarboxamide

ESI(+) MS: m/z 519 (MH⁺).

Example 7 Conversion 6N-[5-(3,5-Difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrabydro-pyran-4-ylamino)-benzamide[(I_(A)), R1═R2═R3═H, R=3,5-difluorophenyl,Ar=4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-phenyl]cpd. 11

To a solution of2-amino-N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-benzamide(1.9 g, 3.98 mmol) in dichloromethane (80 mL) were addedtetrahydro-pyran-4-one (0.55 mL, 5.98 mmol), trifluoroacetic acid (4 mL)and tetramethylammonium triacetoxyborohydride (1.57 g, 5.98 mmol). Themixture was stirred at room temperature overnight, and then moretetramethylammonium triacetoxyborohydride (1.57 g) was added. Afterstirring for additional 3 hours at room temperature the mixture wasdiluted with dichloromethane, washed with 2N sodium hydroxide and brine,dried over sodium sulfate and evaporated to dryness. The crude waspurified by flash chromatography on silica gel usingdichloromethane/methanol/NH₃ 5N in MeOH 96:4:0.5 as the eluant,affording 1.61 g of the title compound (72% yield).

1H-NMR (400 MHz), δ (ppm, DMSO-d6): 1.26-1.43 (m, 2H) 1.86-2.02 (m, 2H)2.23 (s, 3H) 2.42-2.46 (m, 4H) 3.23-3.29 (m, 4H) 3.45-3.54 (m, 2H)3.62-3.75 (m, 1H) 3.82 (dt, J=11.61, 3.83 Hz, 2H) 4.05 (s, 2H) 6.14 (d,J=2.07 Hz, 1H) 6.24 (dd, J=8.90, 2.19 Hz, 1H) 6.94-7.06 (m, 3H) 7.26(dd, J=8.66, 1.46 Hz, 1H) 7.41 (d, J=8.66 Hz, 1H) 7.50 (d, 1H) 7.80 (d,J=9.15 Hz, 1H) 8.29 (d, J=7.68 Hz, 1H) 10.08 (s, 1H) 12.63 (s, 1H)

N-{5-[(3,5-Difluoro-phenyl)-methoxy-methyl]-1H-indazol-3-yl}-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide[(I_(C)), R1═R2═R3═H, R=3,5-difluorophenyl, R′=methyl,Ar=4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-phenyl]cpd. 68

Title compound was isolated as a by-product (about 15%) duringpreparative HPLC purification of the mixed fractions resulted fromcolumn chromatography purification of the previously reportedpreparation ofN-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide1H-NMR (400 MHz), δ (ppm, DMSO-d6): 1.31-1.44 (m, 2H) 1.91-2.01 (m, 2H)2.79 (br. s., 3H) 3.32 (m, 11H) 3.45-3.56 (m, 2H) 3.68-3.78 (m, 1H)3.80-3.88 (m, 2H) 5.48 (s, 1H) 6.22 (d, J=2.07 Hz, 1H) 6.30 (d, J=9.02Hz, 1H) 7.04-7.12 (m, 3H) 7.32 (dd, J=8.78, 1.46 Hz, 1H) 7.45 (d, J=8.90Hz, 1H) 7.64 (s, 1H) 7.86 (d, J=9.02 Hz, 1H) 8.35 (d, J=7.80 Hz, 1H)10.20 (s, 1H) 12.73 (s, 1H) Operating in an analogous way, the followingcompounds were obtained:

2-[(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)amino]-N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methylpiperazin-1-yl)benzamide

ESI(+) MS: m/z 635 (MH⁺).

tert-butyl3-({[2-{[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]carbamoyl}-5-(4-methylpiperazin-1-yl)phenyl]amino}methyl)azetidine-1-carboxylate

ESI(+) MS: m/z 646 (MH⁺).

1-[4-{[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]carbamoyl}-3-(tetrahydro-2H-pyran-4-ylamino)benzyl]piperidinetrifluoroacetate [(I_(A)), R1═R2═R3═H, R=3,5-difluorophenyl,Ar=4-piperidin-1-ylmethyl-2-(tetrahydro-pyran-4-ylamino)-phenyl] cpd.115

1H-NMR (400 MHz), δ (ppm, DMSO-d6): 1.32-1.46 (m, 3H) 1.65-1.93 (m, 5H)1.96-2.04 (m, 2H) 2.81-2.96 (m, 2H) 3.32 (br. s., 2H) 3.44-3.54 (m, 2H)3.63-3.74 (m, 1H) 3.82-3.91 (m, 2H) 4.06 (s, 2H) 4.23 (d, J=5.37 Hz, 2H)6.75-6.81 (m, 1H) 6.94-7.06 (m, 2H) 7.13 (s, 1H) 7.29 (dd, J=8.66, 1.46Hz, 1H) 7.45 (d, J=8.54 Hz, 1H) 7.50 (s, 1H) 7.96 (d, J=8.05 Hz, 1H)8.00 (br. s., 1H) 10.14 (br. s., 1H) 10.54 (s, 1H) 12.77 (br. s., 1H)

N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-{[(2-methoxyethyl)(methyl)amino]methyl}-2-(tetrahydro-2H-pyran-4-ylamino)benzamide[(I_(A)), R1═R2═R3═H, R=3,5-difluorophenyl,Ar=4-{[(2-methoxyethyl)(methyl)amino]methyl}-2-(tetrahydro-pyran-4-ylamino)-phenyl]cpd. 116

1H-NMR (400 MHz), δ (ppm, DMSO-d6): 1.31-1.45 (m, 2H) 1.95 (d, J=11.83Hz, 2H) 2.22 (s, 3H) 2.52-2.57 (m, 2H) 3.26 (s, 3H) 3.43-3.53 (m, 6H)3.64 (dd, J=6.95, 2.93 Hz, 1H) 3.80-3.88 (m, 2H) 4.05 (s, 2H) 6.58 (d,J=7.93 Hz, 1H) 6.79 (s, 1H) 6.95-7.06 (m, 3H) 7.27 (dd, J=8.66, 1.46 Hz,1H) 7.43 (d, J=8.54 Hz, 1H) 7.52 (s, 1H) 7.86 (d, J=8.05 Hz, 1H) 7.96(d, J=7.56 Hz, 1H) 10.39 (s, 1H) 12.71 (s, 1H)

N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(pyrrolidin-1-ylmethyl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide[(I_(A)), R1═R2═R3═H, R=3,5-difluorophenyl,Ar=4-(pyrrolidin-1-ylmethyl)-2-(tetrahydro-pyran-4-ylamino)-phenyl] cpd.117

1H-NMR (400 MHz), δ (ppm, DMSO-d6): 1.31-1.45 (m, 2H) 1.67-1.78 (m, 4H)1.90-1.98 (m, 2H) 2.47 (br. s., 2H) 3.44-3.54 (m, 2H) 3.56 (br. s., 4H)3.59-3.71 (m, 1H) 3.83 (dt, J=11.65, 3.69 Hz, 2H) 4.05 (s, 2H) 6.59 (d,J=8.66 Hz, 1H) 6.77 (s, 1H) 6.92-7.07 (m, 3H) 7.27 (dd, J=8.66, 1.59 Hz,1H) 7.42 (d, J=0.49 Hz, 1H) 7.52 (s, 1H) 7.85 (d, J=8.17 Hz, 1H) 7.95(d, J=7.80 Hz, 1H) 10.39 (s, 1H) 12.71 (s, 1H)

N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(morpholin-4-ylmethyl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide[(I_(A)), R1═R2═R3═H, R=3,5-difluorophenyl,Ar=4-(morpholin-4-ylmethyl)-2-(tetrahydro-pyran-4-ylamino)-phenyl] cpd.118

1H-NMR (400 MHz), δ (ppm, DMSO-d6): 1.30-1.44 (m, 2H) 1.88-2.01 (m, 2H)2.39 (br. s., 4H) 3.45-3.46 (m, 2H) 3.46-3.54 (m, 2H) 3.61 (br. s., 4H)3.65 (d, 1H) 3.84 (d, J=12.32 Hz, 2H) 4.05 (s, 2H) 6.60 (d, J=8.41 Hz,1H) 6.79 (s, 1H) 6.89-7.09 (m, 3H) 7.28 (dd, J=8.72, 1.16 Hz, 1H) 7.43(d, J=8.78 Hz, 1H) 7.51 (s, 1H) 7.87 (d, J=8.05 Hz, 1H) 7.95 (d, J=7.80Hz, 1H) 10.40 (s, 1H) 12.71 (s, 1H)

4-(azetidin-1-ylmethyl)-N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-2-(tetrahydro-2H-pyran-4-ylamino)benzamide[(I_(A)), R1═R2═R3═H, R=3,5-difluorophenyl,Ar=4-(azetidin-1-ylmethyl)-2-(tetrahydro-pyran-4-ylamino)-phenyl] cpd.119

1H-NMR (400 MHz), δ (ppm, DMSO-d6): 1.31-1.43 (m, 2H) 1.90-1.98 (m, 2H)1.98-2.06 (m, 2H) 3.15 (t, J=1.95 Hz, 4H) 3.46-3.54 (m, 4H) 3.61-3.70(m, 1H) 3.79-3.88 (m, 2H) 4.05 (s, 2H) 6.53 (dd, J=8.11, 1.16 Hz, 1H)6.72 (s, 1H) 6.94-7.05 (m, 3H) 7.27 (dd, J=8.60, 1.52 Hz, 1H) 7.43 (d,J=8.66 Hz, 1H) 7.51 (s, 1H) 7.83 (d, J=8.17 Hz, 1H) 7.94 (d, J=7.80 Hz,1H) 10.38 (s, 1H) 12.70 (s, 1H)

N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-{[(2S)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]carbonyl}-2-(tetrahydro-2H-pyran-1-ylamino)benzamide[(I_(A)), R1═R2═R3═H, R=3,5-difluorophenyl,Ar=4-{[(2S)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]carbonyl}-2-(tetrahydro-pyran-4-ylamino)-phenyl]cpd. 127

1H-NMR (400 MHz), δ (ppm, DMSO-d6): ppm 3.44-3.56 (m, 2H) 3.61-3.75 (m,1H) 3.78-3.88 (m, 2H) 4.06 (s, 2H) 4.26 (br. s., 1H) 6.66 (s, 1H) 6.83(s, 1H) 6.95-7.06 (m, 3H) 7.28 (dd, J=8.66, 1.46 Hz, 1H) 7.44 (d, J=8.78Hz, 1H) 7.53 (s, 1H) 7.93 (d, J=8.17 Hz, 1H) 7.97 (br. s., 1H) 10.55 (s,1H) 12.75 (s, 1H)

N-[5-(3,5-difluorobenzyl)-1H-Indazol-3-yl]-4-{[(2R)-2-(pyrrolidin-1-ylmethyl)pyrrolin-1-yl]carbonyl}-2-(tetrahydro-2H-pyran-4-ylamino)benzamide[(I_(A)) R1═R2═R3═H, R=3,5-difluorophenyl,Ar=4-{[(2R)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]carbonyl}-2-(tetrahydro-pyran-4-ylamino)-phenyl]cpd. 128

1H-NMR (400 MHz), δ (ppm, DMSO-d6): ppm 3.44-3.56 (m, 2H) 3.61-3.75 (m,1H) 3.78-3.88 (m, 2H) 4.06 (s, 2H) 4.26 (br. s., 1H) 6.66 (s, 1H) 6.83(s, 1H) 6.95-7.06 (m, 3H) 7.28 (dd, J=8.66, 1.46 Hz, 1H) 7.44 (d, J=8.78Hz, 1H) 7.53 (s, 1H) 7.93 (d, J=8.17 Hz, 1H) 7.97 (br. s., 1H) 10.55 (s,1H) 12.75 (s, 1H)

N¹-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-N⁴-[2-(dimethylamino)ethyl]-N⁴-methyl-2-(tetrahydro-2H-pyran-4-ylamino)benzene-1,4-dicarboxamide[(I_(A)), R1═R2═R3═H, R=3,5-difluorophenyl,Ar=4-({N-[2-(dimethylamino)ethyl]-N-methyl}carbonyl)-2-(tetrahydro-pyran-4-ylamino)-phenyl]cpd. 129

1H-NMR (400 MHz), δ (ppm, DMSO-d6): mixture of rotamers 1.31-1.44 (m,2H) 1.87-1.97 (m, 2H) 3.45-3.52 (m, 2H) 3.62-3.72 (m, 1H) 3.79-3.88 (m,2H) 4.06 (s, 2H) 6.56 (d, J=7.68 Hz, 1H) 6.76 (br. s., 1H) 6.95-7.05 (m,3H) 7.28 (dd, J=8.59, 1.52 Hz, 1H) 7.44 (d, J=8.65 Hz, 1H) 7.54 (s, 1H)7.91-7.99 (m, 2H) 10.56 (s, 1H) 12.75 (s, 1H)

N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-{[4-(propan-2-yl)piperazin-1-yl]carbonyl}-2-(tetrahydro-2H-pyran-4-ylamino)benzamide[(I_(A)), R1═R2═R3═H, R=3,5-difluorophenyl,Ar=4-{[4-(propan-2-yl)piperazin-1-yl]carbonyl}-2-(tetrahydro-pyran-4-ylamino)-phenyl]cpd. 130

1H-NMR (400 MHz), δ (ppm, DMSO-d6): 0.99 (d, J=6.46 Hz, 6H) 1.32-1.43(m, 2H) 1.89-1.97 (m, 2H) 2.36-2.54 (m, 4H) 2.66-2.75 (m, 1H) 3.28-3.37(m, 2H) 3.49 (td, J=1.18, 2.13 Hz, 2H) 3.61 (br. s., 2H) 3.65-3.74 (m,1H) 3.80-3.87 (m, 2H) 4.06 (s, 2H) 6.58 (dd, J=7.98, 1.28 Hz, 1H) 6.77(d, J=0.85 Hz, 1H) 6.95-7.05 (m, 3H) 7.28 (dd, J=8.59, 1.52 Hz, 1H) 7.44(d, J=8.65 Hz, 1H) 7.53 (s, 1H) 7.91-7.95 (m, 1H) 7.94-7.96 (m, 1H)10.56 (s, 1H) 12.75 (s, 1H)

N¹-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-N⁴-[2-(dimethylamino)ethyl]-2-(tetrahydro-2H-pyran-4-ylamino)benzene-1,4-dicarboxamide[(I_(A)), R1═R2═R3═H, R=3,5-difluorophenyl,Ar=4-({N-[2-(dimethylamino)ethyl]}carbonyl)-2-(tetrahydro-pyran-4-ylamino)-phenyl]cpd. 131

1H-NMR (400 MHz), δ (ppm, DMSO-d6): 1.33-1.47 (m, 2H) 1.93-2.00 (m, 2H)2.30 (br. s., 6H) 2.51-2.60 (m, 2H) 3.37-3.44 (m, 2H) 3.46-3.54 (m, 2H)3.73 (d, 1H) 3.85 (dt, J=11.61, 3.76 Hz, 2H) 4.06 (s, 2H) 6.95-7.05 (m,3H) 7.07 (dd, J=8.17, 1.46 Hz, 1H) 7.23 (d, J=1.22 Hz, 1H) 7.28 (dd,J=8.65, 1.58 Hz, 1H) 7.44 (d, J=8.53 Hz, 1H) 7.54 (s, 1H) 7.93 (d,J=7.68 Hz, 1H) 7.96 (d, J=8.29 Hz, 1H) 8.47 (t, J=4.94 Hz, 1H) 10.60 (s,1H) 12.76 (s, 1H)

N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-[(4-methylpiperazin-1-yl)carbonyl]-2-(tetrahydro-2H-pyran-4-ylamino)benzamide[(I_(A)), R1═R2═R3═H, R=3,5-difluorophenyl,Ar=4-[(4-methylpiperazin-1-yl)carbonyl]-2-(tetrahydro-pyran-4-ylamino)-phenyl]cpd. 132

1H-NMR (400 MHz), δ (ppm, DMSO-d6): 1.32-1.43 (m, 2H) 1.93 (d, J=11.70Hz, 2H) 2.22 (s, 3H) 2.33 (m, 4H) 3.45-3.53 (m, 2H) 3.65-3.73 (m, 1H)3.80-3.86 (m, 2H) 4.06 (s, 2H) 6.57 (dd, J=7.98, 1.28 Hz, 1H) 6.77 (d,J=0.98 Hz, 1H) 6.96-7.05 (m, 3H) 7.28 (dd, J=8.59, 1.52 Hz, 1H) 7.44 (d,J=8.53 Hz, 1H) 7.52 (s, 1H) 7.92-7.95 (m, 1H) 7.94-7.97 (m, 1H) 10.56(s, 1H) 12.75 (s, 1H)

N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}-2-(tetrahydro-2H-pyran-4-ylamino)benzamide[(I_(A)), R1═R2═R3═H, R=3,5-difluorophenyl,Ar=4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}-2-(tetrahydro-pyran-4-ylamino)-phenyl]cpd. 133

1H-NMR (400 MHz), δ (ppm, DMSO-d6): 1.25-1.46 (m, 4H) 1.73 (m, 1H) 1.84(m, 1H) 1.93 (d, J=11.46 Hz, 2H) 2.20 (s, 6H) 2.34 (m, 1H) 2.82 (m, 1H)3.04 (m, 1H) 3.42-3.55 (m, 2H) 3.65-3.76 (m, 2H) 3.78-3.88 (m, 2H) 4.06(s, 2H) 4.43 (m, 1H) 6.58 (dd, J=8.05, 1.34 Hz, 1H) 6.78 (d, J=0.85 Hz,1H) 6.94-7.06 (m, 3H) 7.28 (dd, J=8.65, 1.58 Hz, 1H) 7.44 (d, J=8.53 Hz,1H) 7.53 (s, 1H) 7.90-7.96 (m, 2H) 10.55 (s, 1H) 12.74 (s, 1H)

N¹-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-N⁴-(1-methylpiperidin-4-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzene-1,4-dicarboxamide[(I_(A)), R1═R2═R3═H, R=3,5-difluorophenyl,Ar=4-[N-(1-methylpiperidin-4-yl)-carbonyl]-2-(tetrahydro-pyran-4-ylamino)-phenyl]cpd. 134

1H-NMR (400 MHz), δ (ppm, DMSO-d6): 1.32-1.47 (m, 2H) 1.56-1.70 (m, 2H)1.74-1.83 (m, 2H) 1.92-1.99 (m, 2H) 2.02 (br. s., 2H) 2.21 (s, 3H) 2.82(d, J=13.17 Hz, 2H) 3.46-3.54 (m, 2H) 3.67-3.80 (m, 2H) 3.79-3.88 (m,2H) 4.06 (s, 2H) 6.96-7.05 (m, 3H) 7.08 (dd, J=8.17, 1.46 Hz, 1H) 7.21(d, J=1.22 Hz, 1H) 7.28 (dd, J=8.65, 1.46 Hz, 1H) 7.42-7.46 (m, 1H) 7.54(s, 1H) 7.92-7.97 (m, 2H) 8.26 (d, J=7.80 Hz, 1H) 10.60 (s, 1H) 12.77(s, 1H).

Example 8 Preparation of tert-butyl4-{[(2S)-1-methylpyrrolidin-2-yl]methoxy}-2-nitrobenzoate

In a round bottomed three neck flask under argon atmosphere were addedtoluene (15 ml), CsCO₃ (1.6 gr, 5 mmol), phosphine ligand2-(di-tert-butylphosphino)-1,1′-binaphthyl (331 mg, 0.83 mmol) andPd(dba)₂ (380 mgr, 0.66 mmol). The mixture was degassed bubbling argonfor five minutes. Then 4-bromo-2-nitrobenzoic acid tert butyl ester (1gr, 3.31 mmol) and (S)-(−)-1-methyl-2-pyrrolidinemethanol (0.78 ml, 6.62mmol) were added and the mixture was heated to 100° C. for 18 hr. Thereaction was cooled to room temperature, quenched with 30 ml of waterand extracted twice with 25 ml of AcOEt. The organic phases werecollected, dried over Na₂SO₄ and the solvents evaporated to obtain a redoil which was subjected to chromatography purification on a Biotage SP1automated system (90:10 DCM/MeOH (isocratic) to yield the pure titlecompound as a yellowish oil (460 mgr, 1.36 mmol, 41% yield).

ESI(+) MS: m/z 337 (MH⁺).

Operating in an analogous way, the following compounds were obtained:

tert-butyl 4-[(1-methylpiperidin-4-yl)oxy]-2-nitrobenzoate

1H-NMR (400 MHz), δ (ppm, DMSO-d6): 1.48 (9H, s) 1.68 (m, 2H) 1.95 (m,2H) 2.20 (m, 5H) 2.61 (m, 2H) 4.60 (m, 1H) 7.30 (dd, J=8.78, 2.56 Hz,1H) 7.54 (d, J=2.56 Hz, 1H) 7.79 (d, J=8.78 Hz, 1H)

tert-butyl 4-[2-(dimethylamino)ethoxy]-2-nitrobenzoate

1H-NMR (400 MHz), δ (ppm, DMSO-d6): 1.49 (9H, s) 2.22 (s, 6H) 2.65 (t,J=5.61 Hz, 2H) 4.21 (t, J=5.63 Hz, 2H) 7.30 (dd, J=8.78, 2.56 Hz, 1H)7.52 (d, J=2.56 Hz, 1H) 7.80 (d, J=8.78 Hz, 1H)

tert-butyl 4-{[(3S)-1-methylpyrrolidin-3-yl]oxy}-2-nitrobenzoate

ESI(+) MS: m/z 323 (MH⁺).

Preparation of tert-butyl2-amino-4-{[(2S)-1-methylpyrrolidin-2-yl]methoxy}benzoate

Nitro-derivative tert-butyl4-{[(2S)-1-methylpyrrolidin-2-yl]methoxy}-2-nitrobenzoate (460 mgr, 1.37mmol) was dissolved in 20 ml of MeOH, 130 mg of Pd/C 5% and 700 mg (6.3mmol) of HCOONH₄ were added under argon atmosphere. The mixture wasrefluxed at 80° C. for 1 hr then cooled to room temperature and filteredthrough a small pad of celite washing with MeOH. The solvent was thendistilled off and the residue was dissolved in 20 ml of DCM and washedtwice with 20 ml of NaHCO₃ (10%). The collected organic extracts weredried over Na₂SO₄, filtered and evaporated to dryness to yield a brownoil (400 mgr, 1.31 mmol, 95% yield), which was used in the next stepwithout any further purification.

ESI(+) MS: m/z 307 (MH⁺).

Operating in an analogous way, the following compounds were obtained:

tert-butyl 2-amino-4-[(1-methylpiperidin-4-yl)oxy]benzoate

ESI(+) MS: m/z 307 (MH⁺).

tert-butyl 2-amino-4-[2-(dimethylamino)ethoxy]benzoate

1NMR (400 MHz), 6 (ppm, DMSO-d6): 1.51 (s, 9H) 2.21 (s, 6H) 2.61 (t,J=5.79 Hz, 2H) 4.00 (t, J=5.79 Hz, 2H) 6.11 (dd, J=8.96, 2.50 Hz, 1H)6.25 (d, J=2.56 Hz, 1H) 6.60 (s, 2H) 7.56 (d, J=8.90 Hz, 1H)

tert-butyl 2-amino-4-{[(3S)-1-methylpyrrolidin-3-yl]oxy}benzoate

ESI(+) MS: m/z 293 (MH⁺).

Preparation of tert-butyl4-{[(2S)-1-methylpyrrolidin-2-yl]methoxy}-2-(tetrahydro-2H-pyran-4-ylamino)benzoate

Tert-butyl 2-amino-4-{[(2S)-1-methylpyrrolidin-2-yl]methoxy}benzoate(400 mg, 1.3 mmol) was dissolved in 20 ml of DCM under argon atmosphere.Tetrahydro-4H-pyran-4-one (0.19 ml, 2.05 mmol), TFA (0.29 ml, 3.69 mmol)and Me₄BH(OAc)₃, (540 mg, 2.05 mmol) were added. The resulting slurrywas stirred overnight at room temperature then quenched with 15 ml ofNaHCO₃ 10% and extracted twice with 20 ml of DCM. The organic layerswere then dried over Na₂SO₄, filtered off and concentrated to yield ayellow oil (448 mg, 1.15 mmol, 88%) which was used in the next stepwithout any further purification.

ESI(+) MS: m/z 391 (MH⁺).

Operating in an analogous way, the following compounds were obtained:

tert-butyl4-[(1-methylpiperidin-4-yl)oxy]-2-(tetrahydro-2H-pyran-4-ylamino)benzoate

ESI(+) MS: m/z 391 (MH⁺).

tert-butyl4-[2-(dimethylamino)ethoxy]-2-(tetrahydro-2H-pyran-4-ylamino)benzoate

ESI(+) MS: m/z 365 (MH⁺).

tert-butyl4-{[(3S)-1-methylpyrroldin-3-yl]oxy}-2-(tetrahydro-2H-pyran-4-ylamino)benzoate

ESI(+) MS: m/z 377 (MH⁺).

Preparation of tert-butyl4-{[(2S)-1-methylpyrrolidin-2-yl]methoxy}-2-[tetrahydro-2H-pyran-4-yl(trifluoroacetyl)amino]benzoate

Tert-butyl4-{[(2S)-1-methylpyrrolidin-2-yl]methoxy}-2-(tetrahydro-2H-pyran-4-ylamino)benzoate(448 mg, 1.15 mmol) was dissolved in 20 ml of DCM. TEA (0.18 ml, 1.3mmol) and TFAA (0.27 ml, 1.7 mmol) were added and the reaction mixturewas stirred at room temperature for 2 hours and quenched with 15 ml ofNaHCO₃ 10%. The resulting mixture was extracted twice with 20 ml of DCM,dried over Na₂SO₄, filtered and concentrated under vacuum. The crudeproduct was subjected to silica gel chromatographic purification(DCM/MeOH 95:5) to yield a yellow oil (481 mg, 1 mmol, 87%).

1H-NMR (400 MHz), δ (ppm, DMSO-d6): 1.00 (qd, J=12.25, 4.82 Hz, 1H) 1.47(s, 9H) 1.51-1.64 (m, 1H) 1.98 (d, J=12.68 Hz, 2H) 3.83 (ddd, J=31.46,11.34, 4.02 Hz, 2H) 4.51 (tt, J=11.95, 3.90 Hz, 1H) 7.02 (br. s., 1H)7.21 (d, J=6.95 Hz, 1H) 7.95 (d, J=8.78 Hz, 1H)

Operating in an analogous way, the following compounds were obtained:

tert-butyl4-[(1-methylpiperidin-4-yl)oxy]-2-[tetrahydro-2H-pyran-4-yl(trifluoroacetyl)amino]benzoate

ESI(+) MS: m/z 487 (MH⁺).

tert-butyl4-[2-(dimethylamino)ethoxy]-2-[tetrahydro-2H-pyran-4-yl(trifluoroacetyl)amino]benzoate

ESI(+) MS: m/z 461 (MH⁺).

tert-butyl4-{[(3S)-1-methylpyrrolidin-3-yl]oxy}-2-[tetrahydro-2H-pyran-4-yl(trifluoroacetyl)amino]benzoate

ESI(+) MS: m/z 473 (MH⁺).

Preparation of4-{[(2S)-1-methylpyrrolidin-2-yl]methoxy}-2-[tetrahydro-2H-pyran-4-yl(trifluoroacetyl)amino]benzoicacid trifluoroacetate

Tert-butyl4-{[(2S)-1-methylpyrrolidin-2-yl]methoxy}-2-[tetrahydro-2H-pyran-4-yl(trifluoroacetyl)amino]benzoate(480 mg, 1 mmol) was dissolved in 20 ml of DCM. Anhydrous HCl 4M indioxane was added (2.5 ml, 10 mmol). The reaction was stirred at roomtemperature for 5 days after that the HPLC analysis showed the formationof the desired product but with almost 30% of the detrifluoroacetylatedby-product. Solvents were removed under vacuum and the resulting yellowpowder was suspended in 15 ml of DCM and TFAA (0.28 ml, 2 mmol) wasadded. The solid immediately dissolved and the mixture was stirred for 2hours after that the HPLC analysis showed the complete disappearance ofthe by product. Solvents were evaporated to dryness to yield a darkyellow solid which was used in the next synthetic step without anyfurther purification.

ESI(+) MS: m/z 431 (MH⁺).

Operating in an analogous way, the following compounds were obtained:

tert-butyl4-[(1-methylpiperidin-4-yl)oxy-2-tetrahydro-2H-pyran-4-yl(trifluoroacetyl)amino]benzoicacid trifluoroacetate

ESI(+) MS: m/z 431 (MH⁺).

tert-butyl4-[2-(dimethylamino)ethoxy]-2-[tetrahydro-2H-pyran-4-yl(trifluoroacetyl)amino]benzoicacid trifluoroacetate

ESI(+) MS: m/z 405 (MH⁺).

tert-butyl4-{[(3S)-1-methylpyrrolidin-3-yl]oxy}-2-[tetrahydro-2H-pyran-4-yl(trifluoroacetyl)amino]benzoicacid trifluoroacetate

ESI(+) MS: m/z 417 (MH⁺).

Step i′ Preparation ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-{[(2S)-1-methylpyrrolidin-2-yl]methoxy}-2-(tetrahydro-2H-pyran-4-ylamino)benzamide[(I_(A)), R1═R2═R3═H, R=3,5-difluorophenyl,Ar=4-{[(2S)-1-methylpyrrolidin-2-yl]methoxy}-2-(tetrahydro-2H-pyran-4-ylamino)-phenyl]cpd. 94

4-{[(2S)-1-methylpyrrolidin-2-yl]methoxy}-2-[tetrahydro-2H-pyran-4-yl(trifluoroacetyl)amino]benzoicacid trifluoroacetate (1 mmol, 531 mg) was dissolved in DCM and twodrops of anhydrous DMF under nitrogen atmosphere. Oxalyl chloride (0.17ml, 2 mmol) was added and the mixture was stirred at room temperaturefor 2 hours.

Solvents were evaporated to obtain a yellow powder. The solid wasredissolved in THF under an argon atmosphere and cooled at −20° C. DIPEA(0.56 ml, 3.2 mmol) was added.5-(3,5-Difluorobenzyl)-1H-indazol-3-amine, dissolved in 10 mL of dry THFwas then added dropwise in 15′. The reaction mixture was kept at −20° C.for 6 hours then the temperature was allowed to raise at roomtemperature overnight. The reaction was quenched with 15 mL of NaHCO₃ 5%and extracted twice with AcOEt (15 ml). Solvents were then evaporatedand the residue was redissolved in 20 ml of MeOH. TEA (10 mmol, 1.5 ml)was added and the mixture was heated to 65° C. for 3 hr. Then thereaction was cooled to room temperature and the solvents removed toyield the crude product which was purificated by means of silica gelflash chromatography (AcOEt/MeOH/NH₃Aq. 85:15:05) to yield the titlecompound as a white powder (258 mg, 0.45 mmol, 45%).

1H-NMR (400 MHz), δ (ppm, DMSO-d6): 1.28-1.44 (m, 2H) 1.94 (d, J=12.07Hz, 2H) 3.44-3.56 (m, 3H) 3.59-3.73 (m, 1H) 3.77-3.87 (m, 2H) 4.05 (s,2H) 6.23 (dd, 1H) 6.28 (d, J=2.19 Hz, 1H) 6.92-7.06 (m, 3H) 7.27 (dd,J=8.66, 1.59 Hz, 1H) 7.42 (d, J=8.90 Hz, 1H) 7.50 (s, 1H) 7.88 (d,J=8.90 Hz, 1H) 8.27 (d, J=7.80 Hz, 1H) 10.24 (s, 1H) 12.68 (s, 1H)

Operating in an analogous way, the following compounds were obtained:

N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-[(1-methylpiperidin-4-yl)oxy]-2-(tetrahydro-2H-pyran-4-ylamino)benzamide[(I_(A)), R═R2═R3═H, R=3,5-difluorophenyl,Ar=4-[(1-methylpiperidin-4-yl)oxy]-2-(tetrahydro-2H-pyran-4-ylamino)-phenyl]cpd. 95

1H-NMR (400 MHz), δ (ppm, DMSO-d6): 1.36 (ddd, J=9.82, 3.66, 3.48 Hz,2H) 1.70 (m, 2H) 1.85-2.00 (m, 4H) 2.22-2.30 (m, 5H) 2.64-2.79 (m, 2H)3.44-3.54 (m, 2H) 3.58-3.72 (m, 1H) 3.82 (dt, J=11.65, 3.69 Hz, 2H) 4.05(s, 2H) 4.51 (br. s., 1H) 6.20-6.30 (m, 2H) 6.94-7.07 (m, 3H) 7.27 (dd,J=8.60, 1.52 Hz, 1H) 7.42 (d, J=8.54 Hz, 1H) 7.50 (d, J=2.32 Hz, 1H)7.88 (d, J=9.51 Hz, 1H) 8.22 (d, J=7.68 Hz, 1H) 10.24 (s, 1H) 12.68 (s,1H)

N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]4-[2-(dimethylamino)ethoxy]-2-(tetrahydro-2H-pyran-4-ylamino)benzamide[(I_(A)), R1═R2═R3═H, R=3,5-difluorophenyl,Ar=4-[2-(dimethylamino)ethoxy]-2-(tetrahydro-2H-pyran-4-ylamino)-phenyl]cpd. 96

1H-NMR (400 MHz), δ (ppm, DMSO-d6): 1.31-1.44 (m, 2H) 1.94 (d, J=10.73Hz, 2H) 2.42 (br. s., 6H) 2.89 (br. s., 2H) 3.49 (t, J=9.88 Hz, 2H)3.60-3.73 (m, 1H) 3.78-3.88 (m, 2H) 4.05 (s, 2H) 4.19 (t, J=5.24 Hz, 2H)6.25 (dd, J=8.84, 2.38 Hz, 1H) 6.29 (d, J=2.32 Hz, 1H) 6.93-7.06 (m, 3H)7.27 (dd, J=8.60, 1.52 Hz, 1H) 7.43 (d, J=8.78 Hz, 1H) 7.50 (s, 1H) 7.90(d, J=8.78 Hz, 1H) 8.27 (d, J=7.44 Hz, 1H) 10.26 (s, 1H) 12.68 (s, 1H).

N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-{[(3S)-1-methylpyrrolidin-3-yl]oxy}-2-(tetrahydro-2H-pyran-4-ylamino)benzamide[(I_(A)), R1═R2═R3═H, R=3,5-difluorophenyl,Ar=4-{[(3S)-1-methylpyrrolidin-3-yl]oxy}-2-(tetrahydro-2H-pyran-4-ylamino)-phenyl]cpd. 97

1H-NMR (400 MHz), δ (ppm, DMSO-d6): 1.29-1.44 (m, 2H) 1.75-1.86 (m, 1H)1.93 (d, J=10.49 Hz, 2H) 2.32 (s, 4H) 2.44 (br. s., 1H) 2.65-2.78 (m,2H) 2.79-2.88 (m, 1H) 3.44-3.54 (m, 2H) 3.58-3.71 (m, 1H) 3.82 (d,J=11.58 Hz, 2H) 4.05 (s, 2H) 4.96-5.01 (m, 1H) 6.15-6.19 (m, 1H)6.19-6.20 (m, 1H) 6.94-7.06 (m, 3H) 7.26 (dd, J=8.66, 1.59 Hz, 1H) 7.42(d, J=8.54 Hz, 1H) 7.50 (d, J=1.59 Hz, 1H) 7.87 (d, J=8.90 Hz, 1H) 8.23(d, J=7.68 Hz, 1H) 10.24 (s, 1H) 12.67 (s, 1H).

Example 9 Step u Preparation ofN-[5-(3,5-Difluoro-benzyl)-1-trityl-1H-indazol-3-yl]-2-fluoro-5-formyl-benzamide

2-Fluoro-5-formyl-benzoic acid (368 mg, 2.187 mmol) in toluene (22 mL)was treated with thionyl chloride (1.59 mL, 21.87 mmol) and stirredunder reflux temperature for 4 hours. The volatiles were evaporated, theresidue was taken up with toluene (4 mL) and evaporated to drynessleaving an off white solid which was dissolved in dry THF (5 mL) andadded drop-wise to a solution of5-(3,5-difluoro-benzyl)-1-trityl-1H-indazol-3-ylamine (843 mg, 1.68mmol) and DIPEA (0.88 mL, 5.04 mmol) in THF (10 mL), cooled to 4° C. Thereaction was gradually brought to room temperature. After one night, thevolatiles were evaporated. The crude was dissolved in DCM (150 mL) andwashed with aqueous NaHCO₃ (100 mL) then with water and finally withbrine. After drying over sodium sulphate, evaporation and purificationover silica gel (eluent: DCM) 868 mg of title compound as a white solidin 79% yield were obtained.

1H-NMR (400 MHz), δ (ppm, DMSO-d6): 3.98 (s, 2H) 6.34 (d, J=8.66 Hz, 1H)6.89-7.09 (m, 3H) 7.22-7.34 (m, 15H) 7.53-7.64 (m, 1H) 7.66 (s, 1H) 8.14(br. s., 1H) 8.32 (d, J=4.51 Hz, 1H) 10.05 (s, 1H) 11.08 (br. s., 1H).

Step i″ Preparation ofN-[5-(3,5-Difluoro-benzyl)-1H-indazol-3-yl]-2-fluoro-5-formyl-benzamide

N-[5-(3,5-Difluoro-benzyl)-1-trityl-1H-indazol-3-yl]-2-fluoro-5-formyl-benzamide(740 mg, 1.137 mmol) in dry dioxan (25 mL) was treated with 4N HCl indioxan (2.8 mL). The reaction was stirred at room temperature for twodays. The volatile components were evaporated to dryness and the residuewas taken up with Et₂O (10 mL), stirred for 1 hour, filtered withsuction, washed with Et₂O (10 mL), dried at 50° C. under vacuum toafford 358 mg of title compound as a white solid in 77% yield.

1H-NMR (400 MHz), δ (ppm, DMSO-d6): 4.08 (s, 2H) 6.88-7.09 (m, 3H)7.22-7.31 (m, 1H) 7.45 (d, J=8.41 Hz, 1H) 7.62 (t, J=9.57 Hz, 1H) 7.71(s, 1H) 8.12-8.19 (m, 1H) 8.35 (d, J=5.61 Hz, 1H) 10.08 (s, 1H) 10.92(s, 1H) 12.80 (br. s., 1H)

Preparation ofN-[5-(3,5-Difluoro-benzyl)-1H-indazol-3-yl]-2-fluoro-5-(4-methyl-piperazin-1-ylmethyl)-benzamide[(I_(A)), R1═R2═R3═H, R=3,5-difluorophenyl,Ar=2-fluoro-5-(4-methyl-piperazin-1-ylmethyl)-phenyl] cpd. 120

N-[5-(3,5-Difluoro-benzyl)-1H-indazol-3-yl]-2-fluoro-5-formyl-benzamide(150 mg, 0.367 mmol) in THF (4 mL), under a nitrogen atmosphere, at roomtemperature was treated with N-methylpiperazine ((0.039 mL, 0.367 mmol)and then with acetic acid (0.024 mL, 0.422 mmol). After 0.5 hours sodiumtriacetoxyborohydride was added and the reaction was stirred over night.EtOAc (25 mL) and water (25 mL) were added, pH was adjusted to 11 withconcentrated NH₄OH. The organic layer was separated and the aqueouslayer was extracted twice with EtOAc (2×10 mL). The combines organicextracts were dried over sodium sulphate, evaporated to dryness andpurified over silica gel (Eluent: DCM: 7N NH₃ in MeOH 96:4) affording177 mg of title compound.

1H-NMR (400 MHz), δ (ppm, DMSO-d6): 2.18 (br. s., 3H) 2.30-2.46 (m, 8H)3.51 (br. s., 2H) 4.07 (s, 2H) 6.92-7.00 (m, 2H) 6.99-7.06 (m, 1H) 7.28(s, 1H) 7.28-7.35 (m, 1H) 7.44 (d, J=8.53 Hz, 1H) 7.47-7.54 (m, 1H) 7.65(br. s., 1H) 7.67 (br. s., 1H) 10.66 (br. s., 1H) 12.75 (br. s., 1H)

Operating in an analogous way, the following compounds were obtained:

N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-2-fluoro-5-{[(2S)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]methyl}benzamide[(I_(A)), R1═R2═R3═H, R=3,5-difluorophenyl,Ar=2-fluoro-5-{[(2S)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]methyl}-phenyl]cpd. 121

1H-NMR (400 MHz), δ (ppm, DMSO-d6): 1.67 (m, 6H) 1.92 (m, 1H) 2.14 (m,1H) 2.63 (m, 2H) 2.82 (m, 1H) 3.23-3.37 (m, 2H) 4.07 (s, 2H) 4.17 (d,J=14.26 Hz, 1H) 6.93-6.99 (m, 2H) 6.99-7.07 (m, 1H) 7.25-7.28 (m, 1H)7.28-7.33 (m, 1H) 7.44 (d, J=8.65 Hz, 1H) 7.50 (br. s., 1H) 7.66 (br.s., 2H) 10.64 (br. s., 1H) 12.75 (br. s., 1H)

N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-2-fluoro-5-(morpholin-4-ylmethyl)benzamide[(I_(A)), R1═R2═R3═H, R=3,5-difluorophenyl,Ar=2-fluoro-5-(morpholin-4-ylmethyl)-phenyl] cpd. 122

1H-NMR (400 MHz), δ (ppm, DMSO-d6): 2.40 (br. s., 4H) 3.52 (br. s., 2H)3.60 (br. s., 4H) 4.07 (s, 2H) 6.94-6.99 (m, 2H) 6.99-7.07 (m, 1H) 7.27(d, J=8.65 Hz, 1H) 7.33 (d, J=8.53 Hz, 1H) 7.44 (d, J=8.53 Hz, 1H) 7.53(br. s., 1H) 7.67 (br. s., 2H) 10.67 (br. s., 1H) 12.75 (br. s., 1H).

Example 10 Preparation ofN-[5-(3,5-Difluoro-benzyl)-1-trityl-1H-indazol-3-yl]-4-fluoro-isophthalamicacid

N-[5-(3,5-Difluoro-benzyl)-1-trityl-1H-indazol-3-yl]-2-fluoro-5-formyl-benzamide(88 mg, 0.135 mmol) in tert-butanol (1.8 mL) at room temperature wastreated first with 2-methyl-2-butene (0.079 mL, 1.082 mmol) and thenwith sodium chlorite (37 mg, 0.405 mmol) and sodium dihydrogenphosphatein water (0.8 mL) drop-wise. The reaction was stirred over-night, EtOAcwas then added (30 mL) and washed with water (25 mL). The aqueous layerwas extracted twice with EtOAc (2×10 mL). The combined organic layerswere washed with brine, evaporated to dryness to leave 106 mg of titlecompound which was employed in the following step with no need offurther purification.

1H-NMR (400 MHz), δ (ppm, DMSO-d6): 3.98 (s, 2H) 6.33 (d, J=8.53 Hz, 1H)6.78 (br. s., 1H) 6.90-7.07 (m, 3H) 7.20-7.35 (m, 15H) 7.43-7.54 (m, 1H)7.65 (br. s., 1H) 8.13 (br. s., 1H) 8.29 (d, J=3.66 Hz, 1H) 11.01 (s,1H) 13.12 (br. s., 1H)

Preparation ofN-[5-(3,5-Difluoro-benzyl)-1-trityl-1H-indazol-3-yl]-2-fluoro-5-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidine-1-carbonyl)-benzamide

N-[5-(3,5-Difluoro-benzyl)-1-trityl-1H-indazol-3-yl]-4-fluoro-isophthalamicacid (93 mg, 0.139 mmol) in DCM (1.4 mL) was treated with1-hydroxybenzotriazole (25 mg, 0.181 mmol), EDCI (35 mg, 0.181 mmol) and(S)-(+)-1-(2-pyrrolidinylmethyl)pyrrolidine (0.03 mL, 0.1813 mmol).After 1 hour the reaction was diluted with DCM (25 mL) and washed withaqueous NaHCO₃ (5 mL), water (5 mL) and finally with brine. After dryingover sodium sulphate, evaporation of the solvent and purification oversilica gel (eluent: DCM, 7N NH₃ in MeOH 95:5) 92 mg of title compoundwere obtained in 85% yield over two steps.

1H-NMR (400 MHz), δ (ppm, DMSO-d6): 3.97 (s, 2H) 4.26 (br. s., 1H) 6.33(d, J=8.41 Hz, 1H) 6.86-7.09 (m, 4H) 7.15-7.35 (m, 15H) 7.38-7.46 (m,1H) 7.63 (s, 1H) 7.68 (br. s., 1H) 7.82 (br. s., 1H) 10.96 (br. s., 1H)

Step i″N-[5-(3,5-Difluoro-benzyl)-1H-indazol-3-yl]-2-fluoro-5-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidine-1-carbonyl)-benzamide[(I_(A)), R1═R2═R3═H, R=3,5-difluorophenyl,Ar=2-fluoro-5-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidine-1-carbonyl)-phenyl]cpd. 123

N-[5-(3,5-Difluoro-benzyl)-1-trityl-1H-indazol-3-yl]-2-fluoro-5-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidine-1-carbonyl)-benzamide(90 mg, 0.112 mmol) in DCM (1 mL) was treated with TFA (0.17 mL, 2.24mmol). After two hours at room temperature, DCM was added (25 mL) andthe organic phase was washed with aqueous NaHCO₃, water and brine.Drying over sodium sulphate, evaporation and purification of the crudeover silica gel (eluent: DCM, MeOH, 7N NH₃ in MeOH 9:1:0.1) afforded 42mg of title compound.

1H-NMR (400 MHz), δ (ppm, DMSO-d6): 4.07 (s, 2H) 4.29 (br. s., 1H)6.93-6.99 (m, 2H) 6.99-7.06 (m, 1H) 7.27 (dd, J=8.53, 1.34 Hz, 1H) 7.42(br. s., 1H) 7.65-7.74 (m, 2H) 7.85 (br. s., 1H) 10.80 (br. s., 1H)12.77 (br. s., 1H).

Example 11 Step i′ Preparation of methyl4-{[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]carbamoyl}-3-nitrobenzoate

4-(methoxycarbonyl)-2-nitrobenzoic acid (4.8 gr, 21.3 mmol) and thionylchloride (15.5 mL) were stirred in THF dry (130 mL) at 70° C. for 2hours. Volatiles were evaporated and the residue dissolved in drypyridine (100 mL) at 0° C. A solution of5-(3,5-difluoro-benzyl)-1H-indazol-3-ylamine (4.6 mg, 17.76 mmol) in drypyridine (10 mL) was added to the cooled reaction mixture. Temperaturewas allowed to reach room temperature overnight. Reaction was quenchedwith NaHCO₃ sat. sol and extracted with ethyl acetate. Collected organicphases were dried over Na₂SO₄, filtered and evaporated to dryness.Residue was purified by column chromatography over silica gel(DCM/EtOH/7N NH₃ in MeOH=95/5/0.5) affording 5.4 gr (65% yield) of thetitle compound.

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 3.97 (s, 3H) 4.08 (s, 2H) 6.89-7.00(m, 2H) 6.99-7.07 (m, 1H) 7.29 (dd, J=8.66, 1.46 Hz, 1H) 7.45 (d, J=8.66Hz, 1H) 7.76 (s, 1H) 8.01 (d, J=7.93 Hz, 1H) 8.40 (dd, J=7.93, 1.59 Hz,1H) 8.58 (d, J=1.46 Hz, 1H) 11.22 (s, 1H) 12.81 (s, 1H)

Operating in an analogous way, the following compound was obtained:

methyl 4-{[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]carbamoyl}benzoate

ESI(+) MS: m/z 422 (MH⁺).

Preparation of4-{[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]carbamoyl}-3-nitrobenzoicacid

Methyl4-{[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]carbamoyl}-3-nitrobenzoate(5.4 gr, 11.6 mmol) was dissolved in THF (78 mL) and water (52 mL) andtreated at room temperature with LiOH hydrate (730 mg) for 24 hours. THFwas evaporated and the resulting acqueous phase was trated with 5% KHSO₄acqueous solution (100 mL). The so obtained precipitated was filteredoff and dried under vacuum at 60° C. affording the title compoundwithout any further purification.

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 4.08 (s, 2H) 6.92-7.00 (m, 2H)7.00-7.07 (m, 1H) 7.27 (dd, J=8.59, 1.40 Hz, 1H) 7.44 (d, J=8.65 Hz, 1H)7.76 (s, 1H) 7.85 (d, J=7.68 Hz, 1H) 8.30 (dd, J=7.74, 1.28 Hz, 1H) 8.50(d, J=1.22 Hz, 1H) 11.08 (s, 1H) 12.77 (s, 1H)

Operating in an analogous way, the following compound was obtained:

4-{[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]carbamoyl}benzoic acid

ESI(+) MS: m/z 408 (MH⁺).

Preparation ofN-[5-(3,5-Difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazine-1-carbonyl)-2-nitro-benzamide

4-{[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]carbamoyl}-3-nitrobenzoicacid (500 mg, 1.11 mmol) in DMF (10 mL) was treated with1-hydroxybenzotriazole (195 mg, 1.44 mmol), EDCI (276 mg, 1.44 mmol) and1-methylpiperazine (0.16 mL, 1.44 mmol). The reaction was left at roomtemperature over night. The volatiles were removed by evaporation, theresidue was added drop-wise to iced-water (25 mL) with stirring. Ayellow solid was obtained which was extracted with DCM (2×25 mL). Thecombined organic layers were dried over sodium sulphate and evaporatedleaving 590 mg of title compound which was employed in the followingstep without any further purification.

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 2.23 (s, 3H) 2.34 (m, 2H) 2.45 (m,2H) 3.39 (m, 2H) 3.67 (m, 2H) 4.08 (s, 2H) 6.93-6.99 (m, 2H) 6.99-7.07(m, 1H) 7.28 (dd, J=8.59, 1.40 Hz, 1H) 7.45 (d, J=8.53 Hz, 1H) 7.74 (s,1H) 7.87-7.90 (m, 1H) 7.90-7.93 (m, 1H) 8.15 (d, J=0.85 Hz, 1H) 11.10(s, 1H) 12.78 (s, 1H)

Operating in an analogous way, the following compounds were obtained:

N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-{[(2R)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]carbonyl}benzamide[(I_(A)), R1═R2═R3═H, R=3,5-difluorophenyl,Ar=4-{[(2R)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]carbonyl}-phenyl]cpd. 124

1H-NMR (400 MHz), δ (ppm, DMSO-d6): 4.06 (s, 2H) 4.30 (br. s., 1H)6.94-7.00 (m, 2H) 6.99-7.06 (m, 1H) 7.27 (dd, J=8.66, 1.59 Hz, 1H) 7.44(d, J=8.54 Hz, 1H) 7.61 (d, 2H) 7.63 (s, 1H) 8.11 (d, J=8.29 Hz, 2H)10.81 (s, 1H) 12.77 (s, 1H)

N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-{[(2S)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]carbonyl}benzamide[(I_(A)), R1═R2═R3═H, R=3,5-difluorophenyl,Ar=4-{[(2S)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]carbonyl}-phenyl]cpd. 125

1H-NMR (400 MHz), δ (ppm, DMSO-d6): 4.06 (s, 2H) 4.30 (br. s., 1H)6.94-7.00 (m, 2H) 6.99-7.06 (m, 1H) 7.27 (dd, J=8.60, 1.52 Hz, 1H) 7.44(d, J=8.90 Hz, 1H) 7.59-7.65 (m, 3H) 8.11 (d, J=8.17 Hz, 2H) 10.81 (s,1H) 12.77 (s, 1H)

N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-{[4-(pyrrolidin-1-yl)piperidin-1-yl]carbonyl}benzamide[(I_(A)), R1═R2═R3═H, R=3,5-difluorophenyl,Ar=4-{[4-(pyrrolidin-1-yl)piperidin-1-yl]carbonyl}-phenyl] cpd. 126

1H-NMR (400 MHz), δ (ppm, DMSO-d6): 1.41 (m, 2H) 1.70 (m, 4H) 1.94 (m,2H) 2.33 (m, 1H) 2.53 (m, 4H) 3.06 (m, 2H) 3.52 (m, 1H) 4.06 (s, 2H)4.30 m, 1H) 6.94-7.00 (m, 2H) 7.00-7.05 (m, 1H) 7.27 (dd, J=8.66, 1.59Hz, 1H) 7.42-7.46 (m, 1H) 7.54 (d, J=8.29 Hz, 2H) 7.62 (s, 1H) 8.12 (d,J=8.17 Hz, 2H) 10.81 (s, 1H) 12.77 (s, 1H).

Example 12 Preparation of 2-nitro-terephthalic acid 1-tert-butyl ester4-methyl ester

Commercially available 2-nitro-terephthalic acid 4-methyl ester (4.84 g,21.49 mmol) in DCM (54 mL) was treated with tert-butanol (4.05 mL, 42.99mmol), di-tert-butyl dicarbonate (12.19 g, 55.87 g) and DMAP (0.79 g,6.45 mmol). After 4 days at room temperature, the reaction was dilutedwith DCM (100 mL), washed with 1N HCl (100 mL), aqueous NaHCO₃ andfinally with water. After drying over sodium sulphate and evaporation ofthe volatiles, the title compound was obtained as a brownish oil in morethan quantitative yield (6.51 g). The crude was employed in thefollowing step with no further purification.

ESI(+) MS: m/z 282 (MH⁺).

Preparation of 2-nitro-terephthalic acid 1-tert-butyl ester

2-Nitro-terephthalic acid 1-tert-butyl ester 4-methyl ester (21.49 mmol)was dissolved in THF (143 mL) and treated with lithium hydroxidemonohydrate (1.35 g, 32.24 mmol) in water (97 mL). The reaction wasstirred at room temperature for 2 hours then partially evaporated,cooled with an ice/water bath and treated with 1N HCl dropwise (35 mL).Precipitation of a solid occurred. The mixture was then extracted withDCM (150 mL and 2×50 mL). The aqueous phase was further treated with 1NHCl (10 mL) and extracted with DCM (2×50 mL). The combined organiclayers were then washed with water and finally with brine. After dryingover sodium sulphate and evaporation, 5.34 g of title compound wereobtained as a reddish solid in 93% overall yield.

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 1.53 (s, 9H) 7.93 (d, J=7.92 Hz, 1H)8.31 (dd, J=7.92, 1.58 Hz, 1H) 8.42 (d, J=1.34 Hz, 1H) 13.78 (s, 1H)

Preparation of 2-Nitro-4-(piperidine-1-carbonyl)-benzoic acid tert-butylester

2-Nitro-terephthalic acid 1-tert-butyl ester (500 mg, 1.88 mmol) in DCM(18 mL), was treated with 1-hydroxybenzotriazole (0.39 g, 2.43 mmol),EDCI (0.47 g, 2.43 mmol) and piperidine (0.24 mL, 2.43 mmol). After 3hours the reaction was diluted with DCM (50 mL) and washed with aqueousNaHCO₃ (30 mL), water (30 mL) and finally with brine. After drying oversodium sulphate and evaporation of the solvent the title compound wasobtained as a colourless oil in quantitative yield. The crude wasemployed in the following reaction without any further purification.

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 1.45 (br. s., 6H) 1.51 (s, 9H)3.19-3.27 (m, 2H) 3.59 (br. s., 2H) 7.76-7.81 (m, 1H) 7.85-7.89 (m, 1H)8.01 (d, J=1.22 Hz, 1H)

Operating in a way analogous to that described above, the followingcompounds were obtained:

tert-butyl 4-[(2-methoxyethyl)methyl)carbamoyl]-2-nitrobenzoate

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): mixture of rotamers 1.52 (s, 9H)7.77-7.83 (m, 1H) 7.84-7.91 (m, 1H) 8.03 (d, J=0.61 Hz, 1H)

tert-butyl 2-nitro-4-(pyrrolidin-1-ylcarbonyl)benzoate

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 1.52 (s, 9H) 1.78-1.94 (m, 4H)3.37-3.43 (m, 2H) 3.49 (t, J=6.70 Hz, 2H) 7.84-7.90 (m, 1H) 7.91-7.96(m, 1H) 8.12 (d, J=1.34 Hz, 1H)

tert-butyl 4-(azetidin-1-ylcarbonyl)-2-nitrobenzoate

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 1.52 (s, 9H) 2.29 (dt, J=15.51, 7.79Hz, 2H) 4.06-4.12 (m, 2H) 4.31-4.38 (m, 2H) 7.88 (d, J=7.92 Hz, 1H) 8.01(dd, J=7.92, 1.58 Hz, 1H) 8.16 (d, J=1.34 Hz, 1H)

tert-butyl 4-(morpholin-4-ylcarbonyl)-2-nitrobenzoate

ESI(+) MS: m/z 337 (MH⁺).

Preparation of 2-nitro-4-piperidin-1-ylmethyl-benzoic acid hydrochloride

2-Nitro-4-(piperidine-1-carbonyl)-benzoic acid tert-butyl ester (1.87mmol) was dissolved in dry THF and added drop-wise to 3.7 mL of boranetetrahydrofuran complex 1.0 M solution, at room temperature, undernitrogen, with stirring. The reaction was then refluxed for six hours,cooled to room temperature and treated carefully with 2N HCl (10 mL).After stirring for 15 minutes, solid K₂CO₃ was added in portions (1.75g). The mixture was extracted with EtOAc (3×25 mL). The combined organiclayers were dried over sodium sulphate and evaporated leaving an oilthat by HPLC-MS analysis resulted a 4:6 mixture of the tertiary amineand the corresponding borane complex. The mixture was dissolved in DCM(1 mL) and treated with 4N HCl in dioxane (7 mL). After 4 days at roomtemperature, an off white was formed which was filtered, washed withdioxane (5 mL) and dried at 50° C. under vacuum. 0.40 g of titlecompound were obtained in 70% overall yield.

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 1.37-1.80 (m, 5H) 2.90 (br. s., 4H)4.42 (s, 2H) 7.92-7.99 (m, 2H) 8.24 (d, J=0.85 Hz, 1H) 9.99 (br. s., 1H)

4-{[(2-methoxyethyl)(methyl)amino]methyl}-2-nitrobenzoic acidhydrochloride

ESI(+) MS: m/z 269 (MH⁺).

2-nitro-4-(pyrrolidin-1-ylmethyl)benzoic acid hydrochloride

ESI(+) MS: m/z 251 (MH⁺).

4-(morpholin-4-ylmethyl)-2-nitrobenzoic acid hydrochloride

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 2.39 (t, J=4.51 Hz, 4H) 3.59 (t,J=4.63 Hz, 4H) 3.62 (s, 2H) 7.72 (dd, J=7.87, 1.28 Hz, 1H) 7.82 (d,J=7.80 Hz, 1H) 7.87 (d, J=0.98 Hz, 1H)

4-(azetidin-1-ylmethyl)-2-nitrobenzoic acid hydrochloride

ESI(+) MS: m/z 237 (MH⁺).

Step i′ Preparation ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-2-nitro-4-(piperidin-1-ylmethyl)benzamide

2-Nitro-4-piperidin-1-ylmethyl-benzoic acid hydrochloride (440 mg, 1.46mmol) was treated with thionyl chloride (5 mL) and refluxed for 1 hour.Excess of reagent was removed by evaporation followed by evaporationfrom toluene (2×5 mL). The solid was further died under vacuum. The acidchloride was treated with dry pyridine (7 mL), cooled to 4° C. and addedwith 5-(3,5-difluoro-benzyl)-1H-indazol-3-ylamine (315 mg, 1.22 mmol) indry pyridine (3 mL) under a nitrogen atmosphere, with stirring. Afterstirring for a few hours the reaction was left at 0° C. over-night.EtOAc (50 mL) and water (50 mL) were added, pH was adjusted to 9 withconcentrated NH₄OH. The organic layer was separated, dried over sodiumsulphate, evaporated to dryness and purified over silica gel (DCM: MeOH95:5) affording 266 mg of title compound in 43% yield.

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 1.54 (br. s., 6H) 2.39 (br. s., 4H)3.61 (s, 2H) 4.07 (s, 2H) 6.92-6.99 (m, 2H) 6.99-7.06 (m, 1H) 7.26-7.29(m, 1H) 7.44 (d, J=8.53 Hz, 1H) 7.73 (s, 1H) 7.79 (s, 2H) 8.04 (s, 1H)11.01 (s, 1H) 12.75 (s, 1H)

Operating in a way analogous to that described above, the followingcompounds were obtained:

N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-{[(2-methoxyethyl)(methyl)amino]methyl}-2-nitrobenzamide

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 2.24 (s, 3H) 2.60 (t, J=5.67 Hz, 2H)3.26 (s, 3H) 3.50 (t, J=5.73 Hz, 2H) 3.70 (s, 2H) 4.07 (s, 2H) 6.96 (d,J=6.70 Hz, 2H) 6.99-7.07 (m, 1H) 7.24-7.30 (m, 1H) 7.44 (d, J=8.53 Hz,1H) 7.73 (s, 1H) 7.80 (s, 2H) 8.07 (s, 1H) 11.02 (s, 1H) 12.75 (s, 1H)

N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-2-nitro-4-(pyrrolidin-1-ylmethyl)benzamide

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 1.75 (br. s., 4H) 2.46-2.56 (m, 4H)3.77 (br. s., 2H) 4.07 (s, 2H) 6.96 (d, J=6.58 Hz, 2H) 6.99-7.06 (m, 1H)7.25-7.30 (m, 1H) 7.44 (d, J=8.54 Hz, 1H) 7.73 (s, 1H) 7.80 (s, 2H) 8.05(s, 1H) 11.02 (s, 1H) 12.75 (s, 1H)

N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(morpholin-4-ylmethyl)-2-nitrobenzamide

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 2.40-2.46 (m, 4H) 3.60-3.65 (m, 4H)3.66 (s, 2H) 4.07 (s, 2H) 6.90-6.99 (m, 2H) 6.99-7.07 (m, 1H) 7.24-7.29(m, 1H) 7.44 (d, J=8.54 Hz, 1H) 7.73 (s, 1H) 7.81 (s, 2H) 8.07 (s, 1H)11.02 (s, 1H) 12.75 (s, 1H)

4-(azetidin-1-ylmethyl)-N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-2-nitrobenzamide

ESI(+) MS: m/z 478 (MH⁺).

Conversion 4 Preparation of2-Amino-N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-piperidin-1-ylmethylbenzamide

N-[5-(3,5-Difluoro-benzyl)-1H-indazol-3-yl]-2-nitro-4-piperidin-1-ylmethyl-benzamide(255 mg, 0.505 mmol) was suspended in DCM (7 mL) and treated withnBu₄NCl (95 mg, 0.343 mmol). Na₂S₂O₄ (659 mg, 3.029 mmol) in water (3.4mL) was added drop-wise, with stirring. After 2 hours, the volatileswere removed by evaporation, a solid was filtered from the aqueous phaseand dried under vacuum. The solid was treated with 4N HCl in dioxane (12mL) and the solvent was then removed by evaporation. The solid wasdissolved in DCM (100 mL), washed with aqueous K₂CO₃ and then withbrine. After drying over sodium sulphate and removal of the solvent, 248mg of title compound were obtained in more than quantitative yield. Thecrude was employed in the following step with no further purification.

ESI(+) MS: m/z 476 (MH⁺).

Operating in a way analogous to that described above, the followingcompounds were obtained:

2-Amino-N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-{[(2-methoxyethyl)(methyl)amino]methyl}-benzamide

ESI(+) MS: m/z 480 (MH⁺).

2-Amino-N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(pyrrolidin-1-ylmethyl)benzamide

ESI(+) MS: m/z 462 (MH⁺).

2-Amino-N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(morpholin-4-ylmethyl)-benzamide

ESI(+) MS: m/z 478 (MH⁺).

2-Amino-4-(azetidin-1-ylmethyl)-N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-benzamide

ESI(+) MS: m/z 448 (MH⁺).

Example 13 Preparation of tert-butyl4-(4-methylpiperazin-1-yl)-2-[(1-methylpiperidin-4-yl)amino]benzoate

tert-Butyl 2-amino-4-(4-methylpiperazin-1-yl)benzoate (1.5 g, 5.15 mmol)was dissolved in dry dioxane (25 mL) under a nitrogen atmosphere.N-methylpiperidone (0.72 g, 6.18 mmol, 1.2 eq) was added, followed bytrifluoroacetic acid (1.03 mL, 13.39 mmol, 2.6 eq) and sodiumtriacetoxyborohydride (1.72 g, 7.73 mmol, 1.5 eq). The mixture wasstirred at room temperature for 26 hours. During this time extraportions of N-methylpiperidone (0.5 mL, 0.75 eq) and sodiumtriacetoxyborohydride (1.72 g, 7.73 mmol, 1.5 eq) were added. Asaturated aqueous solution of NaHCO₃ was then added and the reactionmixture was concentrated under reduced pressure. 10% ammonium hydroxidewas added until pH 10 and the aqueous phase was extracted withdichloromethane. The organic phase was washed with brine, dried overNa₂SO₄ and evaporated under reduced pressure. After purification bychromatography over silica gel (DCM/MeOH/NH₃ 7% in MeOH 90:8:2) 1.025 gof title compound were obtained as off-white solid (51% yield).

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 1.36-1.47 (m, 2H) 1.50 (s, 9H)1.88-1.98 (m, 2H) 2.09-2.16 (m, 2H) 2.18 (s, 3H) 2.21 (s, 3H) 2.38-2.44(m, 4H) 2.59-2.68 (m, 2H) 3.20-3.26 (m, 4H) 3.37-3.50 (m, 1H) 6.01 (d,J=1.95 Hz, 1H) 6.18 (dd, J=9.08, 2.26 Hz, 1H) 7.56 (d, J=9.02 Hz, 1H)7.68 (d, J=7.56 Hz, 1H)

Operating in an analogous way, the following compound was obtained:

ethyl4-{[2-(tert-butoxycarbonyl)-5-(4-methylpiperazin-1-yl)phenyl]amino}piperidine-1-carboxylate

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 1.19 (t, J=7.50 Hz, 3H) 1.24-1.34(m, 2H) 1.50 (s, 9H) 1.89-2.00 (m, 2H) 2.22 (s, 3H) 2.39-2.45 (m, 4H)3.03-3.16 (m, 2H) 3.20-3.29 (m, 4H) 3.66-3.76 (m, 1H) 3.80-3.90 (m, 2H)4.05 (q, J=7.07 Hz, 2H) 6.07 (d, J=2.07 Hz, 1H) 6.20 (dd, J=9.15, 2.19Hz, 1H) 7.57 (d, J=9.02 Hz, 1H) 7.70 (d, J=7.93 Hz, 1H)

Preparation of tert-butyl4-(4-methylpiperazin-1-yl)-2-[(1-methylpiperidin-4-yl)(trifluoroacetyl)amino]benzoate

tert-butyl4-(4-methylpiperazin-1-yl)-2-[(1-methylpiperidin-4-yl)amino]benzoate(1.02 g, 2.625 mmol) was dissolved in dry dichloromethane (10 mL) undernitrogen atmosphere and the solution was cooled to 0° C. Triethylamine(0.548 mL, 3.938 mmol, 1.5 eq) was added, followed by trifluoroaceticanhydride (0.445 mL, 3.15 mmol, 1.2 eq) and the mixture was stirred at0° C. for 2 hours. It was then diluted with dichloromethane and washedtwice with water. The aqueous phase was back-extracted withdichloromethane. The combined organic layers were dried over Na₂SO₄ andconcentrated under reduced pressure to give 1.18 g of crude product (93%yield), which was used in the following step without furtherpurification.

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 0.93-1.07 (m, 2H) 1.45 (s, 9H)1.48-1.64 (m, 2H) 1.85-2.05 (m, 2H) 2.11 (s, 3H) 2.23 (s, 3H) 2.41-2.47(m, 4H) 2.66-2.87 (m, 2H) 3.27-3.35 (m, 4H) 4.10-4.26 (m, 1H) 6.78 (d,J=2.44 Hz, 1H) 7.05 (dd, J=9.02, 2.56 Hz, 1H) 7.81 (d, J=9.02 Hz, 1H)

Operating in an analogous way, the following compound was obtained:

ethyl4-{[2-(tert-butoxycarbonyl)-5-(4-methylpiperazin-1-yl)phenyl](trifluoroacetyl)amino}piperidine-1-carboxylate

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 0.77-0.93 (m, 1H) 1.13 (t, J=7.07Hz, 3H) 1.34-1.44 (m, 1H) 1.46 (s, 9H) 1.56-1.63 (m, 1H) 2.01-2.10 (m,1H) 2.22 (s, 3H) 2.40-2.44 (m, 4H) 2.78-2.97 (m, 2H) 3.27-3.36 (m, 4H)3.91-4.06 (m, 2H) 3.94-4.01 (m, 2H) 4.37-4.47 (m, 1H) 6.78 (d, J=2.44Hz, 1H) 7.04 (dd, J=9.02, 2.56 Hz, 1H) 7.81 (d, J=9.02 Hz, 1H)

Preparation of4-(4-methylpiperazin-1-yl)-2-[(1-methylpiperidin-4-yl)(trifluoroacetyl)amino]benzoicacid dihydrochloride

tert-Butyl4-(4-methylpiperazin-1-yl)-2-[(1-methylpiperidin-4-yl)(trifluoroacetyl)amino]benzoate(1.18 g, 2.435 mmol) was dissolved in dry dichloromethane (3 mL) undernitrogen atmosphere. A 4 M solution of HCl in dioxane (9.1 mL, 36.4mmol, 15 eq) was then added dropwise and the mixture was stirred for 1.5hours. A sticky solid was formed. 5 more equivalents of HCl were addedand the mixture was stirred for 2 more hours. The solid was filtered,washed with DCM (10 mL) and diethyl ether (10 mL) and dried under vacuumat 60° C. for 2 hours. 1.06 g of title compound were obtained as a beigepowder (87% yield).

ESI(+) MS: m/z 429 (MH⁺).

Operating in an analogous way, the following compound was obtained:

2-{[1-(ethoxycarbonyl)piperidin-4-yl](trifluoroacetyl)amino}-4-(4-methylpiperazin-1-yl)benzoicacid hydrochloride

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 0.83-0.98 (m, 1H) 1.13 (t, J=7.01Hz, 3H) 1.34-1.47 (m, 1H) 1.63 (d, J=10.85 Hz, 1H) 2.04 (d, J=13.66 Hz,1H) 2.84 (s, 3H) 2.88 (m, 2H) 3.16 (m, 4H) 3.52 (m, 2H) 3.94-4.02 (m,2H) 4.05 (m, 4H) 4.34-4.48 (m, 1H) 6.96 (d, J=2.32 Hz, 1H) 7.11 (dd,J=8.90, 2.56 Hz, 1H) 7.91 (d, J=8.90 Hz, 1H) 10.26 (br. s., 1H) 12.79(br. s., 1H)

Step i′ Preparation ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methylpiperazin-1-yl)-2-[(1-methylpiperidin-4-yl)amino]benzamide[(I_(A)), R1═R2═R3═H, R=3,5-difluorophenyl,Ar=4-(4-methylpiperazin-1-yl)-2-[(1-methylpiperidin-4-yl]amino)-phenyl]cpd. 13

4-(4-Methylpiperazin-1-yl)-2-[(1-methylpiperidin-4-yl)(trifluoroacetyl)amino]benzoicacid dihydrochloride (251 mg, 0.501 mmol, 1.3 eq) was suspended in dryTHF (4 mL) under nitrogen atmosphere. Thionyl chloride (0.365 mL, 1.0mmol, 2.6 eq) was added and the mixture was stirred at 70° C. for 1.5hours. The mixture was then evaporated to dryness, taken up withtoluene, evaporated to dryness again and then left for 2 hours at roomtemperature under high vacuum. The acid chloride was then suspended indry pyridine (2 mL) and cooled to 0° C. A solution of5-(3,5-difluorobenzyl)-1H-indazol-3-amine (100 mg, 0.386 mmol, 1 eq) indry pyridine (1.2 mL) was added dropwise and the mixture was stirred at0° C. for 2 hours and then left at 4° C. overnight. It was then dilutedwith water and ethyl acetate. The aqueous phase was basified until pH 10with 30% ammonium hydroxide and extracted with ethyl acetate. Thecombined organic layers were dried over Na₂SO₄ and evaporated to drynessto give 290 mg of crude trifluoroacetamide. The crude product wasdissolved in methanol (7 mL), triethylamine was added (1.3 mL, 9.34mmol, 24 eq) and the solution was refluxed for 1.5 hours. The reactionmixture was evaporated to dryness and purified by chromatography onsilica gel (DCM/MeOH/NH₃ 7% in MeOH 83:17:1). The product was thenslurried in diethyl ether (1 mL) for 30 minutes at room temperature,then filtered and dried at 45° C. under high vacuum for 3 hours. 153 mgof title compound were obtained as pale yellow powder (69% yield).

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 1.33-1.50 (m, 2H) 1.92 (dd, J=9.51,4.02 Hz, 2H) 2.18 (br. s., 3H) 2.21 (br. s., 2H) 2.23 (s, 3H) 2.44 (t,J=4.60 Hz, 4H) 2.61 (br. s., 2H) 3.25 (t, J=4.90 Hz, 4H) 3.41-3.52 (m,1H) 4.04 (s, 2H) 6.08 (d, J=1.95 Hz, 1H) 6.22 (dd, J=8.96, 2.13 Hz, 1H)6.98 (m, 3H) 7.24 (dd, J=8.65, 1.46 Hz, 1H) 7.40 (d, J=8.53 Hz, 1H) 7.49(s, 1H) 7.78 (d, J=9.02 Hz, 1H) 8.26 (d, J=7.44 Hz, 1H) 10.06 (s, 1H)12.62 (s, 1H)

Operating in an analogous way, the following compound was obtained:

ethyl4-{[2-{[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]carbamoyl}-5-(4-methylpiperazin-1-yl)phenyl]amino}piperidine-1-carboxylate[(I_(A)), R1═R2═R3═H, R=3,5-difluorophenyl,Ar=4-(4-methylpiperazin-1-yl)-2-{(1-(ethoxycarbonyl)piperidin-4-yl]amino}-phenyl]cpd. 138

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 1.17 (t, J=7.07 Hz, 3H) 1.21-1.34(m, 2H) 1.87-1.98 (m, 2H) 2.26 (br. s., 3H) 2.45-2.49 (m, 4H) 3.07-3.21(m, 2H) 3.25-3.35 (m, 4H) 3.64-3.73 (m, 1H) 3.76 (ddd, J=13.57, 4.18,3.96 Hz, 2H) 4.02 (q, J=7.03 Hz, 2H) 4.04 (s, 2H) 6.15 (d, J=2.10 Hz,1H) 6.25 (dd, J=9.11, 2.10 Hz, 1H) 6.92-7.05 (m, 3H) 7.25 (dd, J=8.57,1.52 Hz, 1H) 7.41 (d, J=8.57 Hz, 1H) 7.47 (s, 1H) 7.80 (d, J=9.11 Hz,1H) 8.31 (d, J=7.93 Hz, 1H) 10.09 (s, 1H) 12.63 (s, 1H)

Preparation ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methylpiperazin-1-yl)-2-(piperidin-4-ylamino)benzamide[(I_(A)), R1═R2═R3═H, R=3,5-difluorophenyl,Ar=4-(4-methylpiperazin-1-yl)-2-[(piperidin-4-yl)amino]-phenyl] cpd. 139

ethyl4-{[2-{[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]carbamoyl}-5-(4-methylpiperazin-1-yl)phenyl]amino}piperidine-1-carboxylate(198 mg, 0.313 mmol) were dissolved in 62% aqueous HBr (4 mL) in a screwcap pirex tube and stirred at 70° C. for 1 hour. The mixture was thendiluted with water and 30% ammonium hydroxide and extracted with ethylacetate. The organic phase was dried over Na₂SO₄ and concentrated todryness. After purification by chromatography on silica gel(DCM/MeOH/NH₃ 7% in MeOH, 80:10:10) 127 mg of pure product were obtained(72% yield). The product was slurried with ethyl acetate, filtered,washed with n-hexane and dried at 45° C. under high vacuum for 3 hoursto give 88 mg of title compound as white solid.

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 1.16-1.31 (m, J=12.50, 10.20, 10.20,3.66 Hz, 2H) 1.89 (dq, J=12.50, 3.40 Hz, 2H) 2.22 (s, 3H) 2.43 (t,J=4.76 Hz, 4H) 2.63 (ddd, J=12.59, 10.27, 2.62 Hz, 2H) 2.92 (dt,J=12.53, 3.92 Hz, 2H) 3.25 (t, J=4.63 Hz, 4H) 3.46-3.57 (m, 1H) 4.04 (s,2H) 6.09 (d, J=2.07 Hz, 1H) 6.22 (dd, J=9.02, 2.07 Hz, 1H) 6.93-7.04 (m,3H) 7.24 (dd, J=8.66, 1.59 Hz, 1H) 7.40 (d, J=8.66 Hz, 1H) 7.48 (br. s.,1H) 7.78 (d, J=9.02 Hz, 1H) 8.24 (d, J=7.80 Hz, 1H) 10.04 (s, 1H) 12.62(s, 1H).

Example 14 Preparation of1-[1-(tert-butoxycarbonyl)piperidin-4-yl]-1H-pyrazole-4-carboxylic acid

A mixture of ethyl 1H-pyrazole-4-carboxylate (700 mg, 5 mmol) and NaH60% (6 mmol) was stirred under nitrogen at 0° C. for 1 hour in dry DMF(15 mL). tert-Butyl 4-[(methylsulfonyl)oxy]piperidine-1-carboxylate(1.53 gr, 5.5 mmol) dissolved in 4 mL of dry DMF was added and theresulting solution was heated at 100° C. overnight. Reaction mixture wasquenched with water and extracted (×3) with ethyl acetate. Collectedorganic phases were dried over Na₂SO₄, filtered and evaporated todryness. Residue was dissolved in MeOH (20 mL) and water (5 mL) and KOH(1.12 gr, 20 mmol) was added. The resulting solution was stirred at roomtemperature 24 hours, then solvents removed under reduced pressure. Theresidue was taken-up with AcOEt and KHSO₄ 5% solution. Acqueous phasewas extracted with EtOAc several times. Collected organic phases weredried with Na₂SO₄, filtered and evaporated to dryness affording 600 mgof the title compound.

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 1.42 (s, 9H) 1.73-1.87 (m, 2H)1.96-2.03 (m, 2H) 2.82-2.99 (m, 2H) 4.04 (d, J=12.93 Hz, 2H) 4.34-4.47(m, 1H) 7.81 (s, 1H) 8.29 (s, 1H) 12.26 (br. s., 1H)

Step i′ Preparation ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-1-(piperidin-4-yl)-1H-pyrazole-4-carboxamidehydrochloride [(I_(A)), R1═R2═R3═H, R=3,5-difluorophenyl,Ar=(piperidin-4-yl)-1H-pyrazole] cpd. 102

1-[1-(tert-butoxycarbonyl)piperidin-4-yl]-1H-pyrazole-4-carboxylic acid(134 mg, 0.45 mmol) and oxalyl chloride (0.6 mmol) were stirred in DCMdry (5 mL) at room temperature overnight. Volatiles were evaporated andthe residue dissolved in dry pyridine (5 mL) at 0° C. A solution of5-(3,5-difluoro-benzyl)-1H-indazol-3-ylamine (100 mg, 0.38 mmol) in drypyridine (2 mL) was added to the cooled reaction mixture. After 1 hour,reaction was quenched with NaHCO₃ sat. sol and extracted with ethylacetate. Collected organic phases were dried over Na₂SO₄, filtered andevaporated to dryness. Residue was purified by column chromatographyover silica gel (DCM/EtOH/NH₃ 5N in MeOH=1000/50/1) affording 87 mg ofBoc-protected derivative which was dissolved in 2 mL of dioxane andtrated with 0.4 mL of 4M HCl in dioxane. Volatiles were evaporatedaffording 65 mg of the title compound.

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 2.10-2.23 (m, 2H) 2.22-2.31 (m, 2H)3.03-3.19 (m, 2H) 3.32-3.49 (m, 2H) 4.05 (s, 2H) 4.54-4.63 (m, 1H)6.92-6.98 (m, 2H) 6.98-7.05 (m, 1H) 7.25 (dd, J=8.59, 1.65 Hz, 1H)7.40-7.44 (m, 1H) 7.63 (d, J=0.61 Hz, 1H) 8.16 (s, 1H) 8.49 (s, 1H)8.65-8.77 (m, 1H) 8.82-8.96 (m, 1H) 10.44 (s, 1H) 12.71 (br. s., 1H)

Example 15 Step i′ Preparation ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-2-[(cis-4-hydroxycyclohexyl)amino]-4-(4-methylpiperazin-1-yl)benzamide[(I_(A)), R1═R2═R3═H, R=3,5-difluorophenyl,Ar=4-(4-methyl-piperazin-1-yl)-2-[(cis-4-hydroxycyclohexyl)amino]-phenyl]cpd. 103

4-(4-methylpiperazin-1-yl)-2-[{cis-4-[(phenylcarbonyl)oxy]cyclohexyl}(trifluoroacetyl)amino]benzoicacid hydrochloride (1.03 gr, 1.94 mmol) and oxalyl chloride (3.88 mmol)were stirred in DCM dry (20 mL) and a few drops of dry DMF at 0° C.,temperature was allowed to reach room temperature in 2 hours. Volatileswere evaporated and the residue dissolved in dry pyridine (25 mL) at 0°C. A solution of 5-(3,5-difluoro-benzyl)-1H-indazol-3-ylamine (387 mg,1.49 mmol) in dry pyridine (6 mL) was added to the cooled reactionmixture. Temperature was allowed to reach room temperature overnightReaction was quenched with NaHCO₃ sat. sol and extracted with ethylacetate. Collected organic phases were dried over Na₂SO₄, filtered andevaporated to dryness. Residue was purified by column chromatographyover silica gel (DCM/AcOEt/EtOH=100/10/15). The so obtained derivative,was dissolved in MeOH (200 mL) and water (20 mL) and treated at 60° C.with LiOH hydrate (160 mg, 3.8 mmol) for 4 hours. MeOH was evaporatedand the resulting acqueous phase was extracted with EtOAc. Collectedorganic phases were dried over Na₂SO₄, filtered and evaporated todryness. Residue was purified by column chromatography over silica gel(DCM/EtOH/NH₃ 5N in MeOH=100/10/2) affording 233 mg of title compound.

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 1.41-1.70 (m, 8H) 2.24 (s, 3H) 2.45(br. s., 4H) 3.22-3.29 (m, 4H) 3.58 (d, J=10.61 Hz, 2H) 4.05 (s, 2H)4.43 (d, J=3.78 Hz, 1H) 6.09 (d, J=1.95 Hz, 1H) 6.22 (dd, J=8.96, 2.13Hz, 1H) 6.94-7.04 (m, 3H) 7.25 (dd, J=8.65, 1.58 Hz, 1H) 7.41 (d, J=8.53Hz, 1H) 7.51 (s, 1H) 7.79 (d, J=9.14 Hz, 1H) 8.39 (d, J=7.68 Hz, 1H)10.04 (s, 1H) 12.63 (s, 1H)

Operating in a way analogous to that described above, the followingcompound was obtained:

N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-2-[(trans-4-hydroxycyclohexyl)amino]-4-(4-methylpiperazin-1-yl)benzamide[(I_(A)), R1═R2═R3═H, R=3,5-difluorophenyl,Ar=4-(4-methyl-piperazin-1-yl)-2-[(trans-4-hydroxycyclohexyl)amino]-phenyl]cpd. 104

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 1.10-1.22 (m, 2H) 1.29-1.41 (m, 2H)1.78-1.83 (m, 2H) 1.94-2.03 (m, 2H) 2.24 (s, 3H) 2.42-2.48 (m, 4H)3.23-3.28 (m, 4H) 3.34-3.42 (m, 1H) 3.43-3.52 (m, 1H) 4.04 (s, 2H) 4.53(d, J=4.14 Hz, 1H) 6.09 (d, J=2.07 Hz, 1H) 6.21 (dd, J=9.02, 2.19 Hz,1H) 6.95-7.04 (m, 3H) 7.25 (dd, J=8.53, 1.58 Hz, 1H) 7.40 (d, J=8.53 Hz,1H) 7.48 (s, 1H) 7.77 (d, J=9.14 Hz, 1H) 8.17 (d, J=7.80 Hz, 1H) 10.04(s, 1H) 12.61 (s, 1H)

Example 16 Preparation ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-2-[(2-hydroxyethyl)amino]-4-(4-methylpiperazin-1-yl)benzamide[(I_(A)), R1═R2═R3═H, R=3,5-difluorophenyl,Ar=4-(4-methyl-piperazin-1-yl)-2-[(2-hydroxyethyl)amino]-phenyl] cpd.105

2-[(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)amino]-N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methylpiperazin-1-yl)benzamide(126 mg, 0.2 mmol) was dissolved in dry THF (3 mL) and 1M TBAF in THF(0.24 mL) was added at 0° C. The resulting solution was stirredovernight at room temperature. Reaction was quenched with water andextracted with ethyl acetate. Collected organic phases were dried overNa₂SO₄, filtered and evaporated to dryness. Residue was purified bycolumn chromatography over silica gel (DCM/EtOH/NH₃ 5N in MeOH=85/15/1)affording 83 mg of title compound.

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 2.34 (br. s., 3H) 2.51-2.65 (m, 4H)3.20 (q, J=5.57 Hz, 2H) 3.25-3.36 (m, 4H) 3.60 (q, J=5.53 Hz, 2H) 4.05(s, 2H) 4.74 (t, J=5.18 Hz, 1H) 6.09 (d, J=2.07 Hz, 1H) 6.25 (dd,J=8.90, 2.19 Hz, 1H) 6.94-6.99 (m, 2H) 6.99-7.04 (m, 1H) 7.23 (dd,J=8.66, 1.58 Hz, 1H) 7.41 (d, J=8.65 Hz, 1H) 7.51 (s, 1H) 7.79 (d,J=9.02 Hz, 1H) 8.22 (t, J=5.18 Hz, 1H) 10.06 (s, 1H) 12.62 (s, 1H).

Example 17 Preparation of2-[(azetidin-3-ylmethyl)amino]-N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methylpiperazin-1-yl)benzamide[(I_(A)), R1═R2═R3═H, R=3,5-difluorophenyl,Ar=4-(4-methyl-piperazin-1-yl)-2-[(azetidin-3-ylmethyl)amino]-phenyl]cpd. 106

tert-butyl3-({[2-{[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]carbamoyl}-5-(4-methylpiperazin-1-yl)phenyl]amino}methyl)azetidine-1-carboxylate(289 mg, 0.45 mmol) was dissolved in DCM (3 mL) and TFA (0.7 mL) wasadded. The resulting reaction solution was stirred overnight at roomtemperature. The mixture was diluted with DCM and extracted with 10%acqueous NH₃. Organic phase was evaporated. Reverse phase columnchromatography purification afforded 104 mg of the title compound.

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 2.24 (s, 3H) 2.42-2.47 (m, 4H)2.80-2.90 (m, 1H) 3.26-3.38 (m, 4H) 3.58 (t, J=7.86 Hz, 2H) 4.04 (s, 2H)6.08 (d, J=2.32 Hz, 1H) 6.25 (dd, J=8.96, 2.13 Hz, 1H) 6.94-7.00 (m, 2H)6.98-7.04 (m, 1H) 7.25 (dd, J=8.65, 1.58 Hz, 1H) 7.39-7.43 (m, 1H) 7.49(d, J=0.61 Hz, 1H) 7.80 (d, J=8.90 Hz, 1H) 8.16 (t, J=5.06 Hz, 1H) 10.07(br. s., 1H) 12.63 (br. s., 1H)

Preparation ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-2-{[(1-methylazetidin-3-yl)methyl]amino}-4-(4-methylpiperazin-1-yl)benzamide[(I_(A)), R1═R2═R3═H, R=3,5-difluorophenyl,Ar=4-(4-methyl-piperazin-1-yl)-2-[(1-methylazetidin-3-ylmethyl)amino]-phenyl]cpd. 107

To a solution of2-[(azetidin-3-ylmethyl)amino]-N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methylpiperazin-1-yl)benzamide(100 mg, 0.14 mmol) in dichloromethane (2 mL) were added formaldehyde 37wt. % in water (0.014 mL, 0.168 mmol), TEA (0.4 mmol) and sodiumtriacetoxyborohydride (45 mg, 0.21 mmol). The mixture was stirred atroom temperature overnight, diluted with dichloromethane, washed withacqueous NaHCO₃ sat.sol., water and brine. Organic phase was dried oversodium sulfate and evaporated to dryness. The crude was purified byflash chromatography on silica gel using dichloromethane/methanol/NH₃ 5Nin MeOH 100:10:1 as the eluant, affording 5 mg of the title compound.

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 2.26 (s, 3H) 2.47 (br. s., 4H) 2.62(s, 3H) 2.84-2.99 (m, 1H) 3.27-3.34 (m, 4H) 3.36-3.46 (m, 2H) 3.52-3.62(m, 2H) 3.80-3.90 (m, 2H) 4.04 (s, 2H) 6.09 (d, J=2.07 Hz, 1H) 6.28 (dd,J=9.02, 2.07 Hz, 1H) 6.93-6.99 (m, 2H) 6.99-7.05 (m, 1H) 7.25 (dd,J=8.59, 1.52 Hz, 1H) 7.41 (d, J=8.65 Hz, 1H) 7.50 (s, 1H) 7.81 (d,J=9.14 Hz, 1H) 8.25 (t, J=5.49 Hz, 1H) 10.12 (s, 1H) 12.64 (s, 1H).

Example 18 Preparation of 4-nitro-2-(tetrahydro-pyran-4-ylamino)-benzoicacid

4-Nitro-2-(tetrahydro-pyran-4-ylamino)-benzoic acid ethyl ester (11.2 g,38 mmol) was dissolved in 200 mL of ethanol at 60° C. then 2N NaOH wasadded (40 mL, 80 mmol). The mixture was stirred at 60° C. for 4 hours,then the solvent removed under reduced pressure. The residue wastaken-up with 200 mL of water and the mixture brought to acidic pH with2N HCl (35 mL). The precipitated yellow solid was filtered, washed withplenty of water and dried in oven at 40° C. affording the title compound(9.3 g).

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 13.49 (bs, 1H), 8.17 (bd, 1H), 8.04(d, J=8.7 Hz, 1H), 7.54 (d, J=2.2 Hz, 1H), 7.32 (dd, J1=8.7 HZ, J2=2.2Hz, 1H), 3.90-3.78 (m, 3H), 3.54 (m, 2H), 1.98 (m, 2H), 1.46 (m, 2H).

Preparation of4-nitro-2-[(tetrahydro-pyran-4-yl)-(2,2,2-trifluoro-acetyl)-amino]-benzoicacid

To 30 mL of trifluoroacetic anhydride was added4-nitro-2-(tetrahydro-pyran-4-ylamino)-benzoic acid (9.1 g, 34.2 mmol)in small portions, at room temperature. The mixture was stirred at roomtemperature for 1 hour then evaporated to dryness. The residue (brownoil) was treated with 200 mL of water and vigorously stirred for 3 hoursat room temperature. The white solid thus formed was filtered, washedwith plenty of water and dried in oven at 40° C. affording the titlecompound (11.8 g).

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 13.52 (bs, 1H), 8.45 (dd, J1=8.5 Hz,J2=2.3 Hz, 1H), 8.32 (d, J=2.3 Hz, 1H), 8.26 (d, J=8.5 Hz, 1H), 4.58 (m,1H), 3.84 (m, 2H), 3.45-3.2 (m, 2H), 1.98 (m, 1H), 1.59 (m, 1H), 1.49(m, 1H), 1.14 (m, 1H).

Step i′ Preparation ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-nitro-2-[tetrahydro-2H-pyran-4-yl(trifluoroacetyl)amino]benzamide

4-nitro-2-[(tetrahydro-pyran-4-yl)-(2,2,2-trifluoro-acetyl)-amino]-benzoicacid (3.62 g, 10 mmol) and oxalyl chloride (3.8 mL, 30 mmol) werestirred in DCM dry (120 mL) and a few drops of dry DMF at roomtemperature for 2 hours Volatiles were evaporated and the residuedissolved in dry pyridine (50 mL) at 0° C. A solution of5-(3,5-difluoro-benzyl)-1H-indazol-3-ylamine (2 gr, 7.72 mmol) in drypyridine (20 mL) was added to the cooled reaction mixture under nitrogenatmosphere. The resulting mixture was allowed to react overnight at roomtemperature, then the solvent removed under reduced pressure. Theresidue was taken-up with EtOAc and washed with acqueous NaHCO₃sat.sol., water and brine. Organic phase was dried over sodium sulfateand evaporated to dryness. The crude was purified by flashchromatography on silica gel using AcOEt/Hexane 7:3 as the eluant,affording 3.9 g of the title compound.

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 1.38-1.57 (m, 2H) 1.65-1.74 (m, 1H)1.91-1.98 (m, 1H) 3.25-3.44 (m, 2H) 3.70-3.78 (m, 1H) 3.87 (dd, J=11.92,4.09 Hz, 1H) 4.04 (s, 2H) 4.47-4.58 (m, 1H) 6.98 (d, J=1.34 Hz, 2H)6.99-7.06 (m, 1H) 7.31 (dd, J=8.68, 1.47 Hz, 1H) 7.45 (d, J=8.56 Hz, 1H)7.54 (s, 1H) 8.20 (d, J=8.56 Hz, 1H) 8.36 (d, J=2.32 Hz, 1H) 8.51 (dd,J=8.56, 2.08 Hz, 1H) 11.28 (s, 1H) 12.85 (s, 1H)

Conversion 4 Preparation ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-amino-2-[tetrahydro-2H-pyran-4-yl(trifluoroacetyl)amino]benzamide

A mixture ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-nitro-2-[tetrahydro-2H-pyran-4-yl(trifluoroacetyl)amino]benzamide(3.86 g, 6.4 mmol), cyclohexene (10 mL), dioxane (70 mL) and 10% Pd/C(0.42 g) was stirred at 100° C. for 4 hours. The reaction mixture wasfiltered over a celite pad washing thoroughly with THF and MeOH. Afterevaporation of the organic phase, purification of the crude bychromatography over silica gel (DCM/EtOH 9/1) gave 2.75 g of titlecompound (82% yield).

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 1.29 (qd, J=12.28, 4.63 Hz, 1H) 1.56(qd, J=12.19, 4.51 Hz, 1H) 1.62 (ddd, J=12.93, 3.47, 2.01 Hz, 1H) 1.84(ddd, J=12.47, 3.93, 2.01 Hz, 1H) 3.33 (m, 2H) 3.77 (dd, J=11.58, 4.39Hz, 1H) 3.88 (dd, J=11.65, 4.33 Hz, 1H) 4.00 (s, 2H) 4.43 (tt, J=11.93,3.86 Hz, 1H) 5.96 (s, 2H) 6.50 (d, J=2.32 Hz, 1H) 6.68 (dd, J=8.47, 2.26Hz, 1H) 6.89-6.97 (m, 2H) 7.01 (tt, J=9.43, 2.33 Hz, 1H) 7.25 (dd, 1H)7.39 (m, 2H) 7.68 (d, J=8.54 Hz, 1H) 10.33 (s, 1H) 12.64 (s, 1H)

Conversion 6 Preparation of tert-butyl3-{[(4-{[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]carbamoyl)}-3-[tetrahydro-2H-pyran-4-yl(trifluoroacetyl)amino]phenyl)amino]methyl}azetidine-1-carboxylate

To a solution ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-amino-2-[tetrahydro-2H-pyran-4-yl(trifluoroacetyl)amino]benzamide(240 mg, 0.42 mmol) in dichloromethane (20 mL) were added tert-butyl3-formylazetidine-1-carboxylate (116 mg, 0.63 mmol), trifluoroaceticacid (0.32 mL) and tetramethylammonium triacetoxyborohydride (165 mg g,0.63 mmol). The mixture was stirred at room temperature overnight, thendiluted with dichloromethane, washed with NaHCO₃ sat.sol. and brine,dried over sodium sulfate and evaporated to dryness.

ESI(+) MS: m/z 743 (MH⁺).

Operating in a way analogous to that described above, the followingcompound was obtained:

N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-[(1-methylpiperidin-4-yl)amino]-2-[tetrahydro-2H-pyran-4-yl(trifluoroacetyl)amino]benzamide

ESI(+) MS: m/z 671 (MH⁺).

Preparation of tert-butyl3-({[4-{[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]carbamoyl}-3-(tetrahydro-2H-pyran-4-ylamino)phenyl]amino}methyl)azetidine-1-carboxylate

tert-butyl3-{[(4-{[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]carbamoyl}-3-[tetrahydro-2H-pyran-4-yl(trifluoroacetyl)amino]phenyl)amino]methyl}azetidine-1-carboxylate(760 mg, 1.02 mmol) was dissolved in MeOH (12 mL) and TEA (4 mL) andstirred at room temperature overnight. Volatiles were evaporated and theresidue was taken-up with DCM and washed with brine. Organic phase wasdried over sodium sulfate and evaporated to dryness.

ESI(+) MS: m/z 647 (MH⁺).

Operating in a way analogous to that described above, the followingcompound was obtained:

N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-[1-methylpiperidin-4-yl)amino]-2-[tetrahydro-2H-pyran-ylamino]benzamide[(I_(A)), R1═R2═R3═H, R=3,5-difluorophenyl,Ar=4-[(1-methylpiperidin-4-yl)amino]-2-[tetrahydro-2H-pyran-4-ylamino]-phenyl]cpd. 108

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 1.28-1.50 (m, 4H) 1.80-1.99 (m, 4H)2.06 (t, J=12.54 Hz, 2H) 2.19 (s, 3H) 2.75 (d, J=12.19 Hz, 2H) 3.40 (m,1H) 3.45 (ddd, J=11.83, 10.12, 2.32 Hz, 2H) 3.83 (dt, J=11.68, 3.86 Hz,2H) 4.03 (s, 2H) 5.87 (d, J=1.71 Hz, 1H) 5.90 (dd, J=8.78, 1.95 Hz, 1H)5.93 (d, J=7.93 Hz, 1H) 5.95 (s, 1H) 6.98 (m, 3H) 7.24 (dd, J=8.66, 1.59Hz, 1H) 7.39 (d, J=8.54 Hz, 1H) 7.47 (br. s., 1H) 7.69 (d, J=8.90 Hz,1H) 8.30 (d, J=7.44 Hz, 1H) 9.88 (s, 1H) 12.57 (s, 1H)

Preparation of4-[(azetidin-3-ylmethyl)amino]-N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-2-(tetrahydro-2H-pyran-4-ylamino)benzamide[(I_(A)), R1═R2═R3═H, R=3,5-difluorophenyl,Ar=4-[(azetidin-3-ylmethyl)amino]-2-[tetrahydro-2H-pyran-4-ylamino]phenyl]cpd. 109

tert-butyl3-({[4-{[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]carbamoyl}-3-(tetrahydro-2H-pyran-4-ylamino)phenyl]amino}methyl)azetidine-1-carboxylate(738 mg, 1.1 mmol) was dissolved in DCM (12 mL) and TFA (3 mL) wasadded. The resulting reaction solution was stirred for 3 hours at roomtemperature. The mixture was diluted with DCM and extracted with 10%acqueous NH₃. Acqueous phase was extracted several time with DCM.Collected organic phases were washed with brine, dried over sodiumsulfate and evaporated to dryness. Column chromatography purification onsilica gel using dichloromethane/methanol/NH₃ 5N in MeOH 70:30:1 as theeluant, afforded 150 mg of the title compound.

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 1.30-1.42 (m, 2H) 1.87-2.00 (m, 2H)2.77-2.88 (m, 1H) 3.24-3.33 (m, 4H) 3.42-3.53 (m, 2H) 3.53-3.60 (m, 3H)3.78-3.88 (m, 2H) 4.05 (s, 2H) 5.86 (s, 1H) 5.90 (d, J=8.66 Hz, 1H)6.07-6.13 (m, 1H) 6.95-7.04 (m, 3H) 7.25 (dd, J=8.60, 1.52 Hz, 1H) 7.40(d, J=8.66 Hz, 1H) 7.48 (s, 1H) 7.70 (d, J=8.78 Hz, 1H) 8.35 (d, J=7.19Hz, 1H) 9.90 (s, 1H) 12.59 (br. s., 1H).

Example 19 Step i′ Preparation of2,6-dichloro-N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]pyridine-3-carboxamide

2,6-dichloropyridine-3-carboxylic acid (480 mg, 2.5 mmol) and thionylchloride (0.28 mL, 3.75 mmol) were heated in toluene dry (120 mL) and afew drops of dry DMF at 90° C. for 2 hours Volatiles were evaporated andthe residue dissolved in dry pyridine (15 mL) at 0° C. under nitrogenatmosphere. A solution of 5-(3,5-difluoro-benzyl)-1H-indazol-3-ylamine(518 mg, 2 mmol) in dry pyridine (7 mL) was added to the cooled reactionmixture. The resulting mixture was allowed to react overnight at roomtemperature, then the solvent removed under reduced pressure. Theresidue was taken-up with EtOAc and washed with acqueous NaHCO₃sat.sol., water and brine. Organic phase was dried over sodium sulfateand evaporated to dryness. The crude was purified by flashchromatography on silica gel using DCM/EtOH 100:4 as the eluant,affording 300 mg of the title compound.

1H-NMR (400 MHz), δ (ppm, DMSO-d): 4.09 (s, 2H) 6.93-7.01 (m, 2H) 7.04(tt, J=9.39, 2.32 Hz, 1H) 7.29 (dd, J=8.54, 1.34 Hz, 1H) 7.45 (d, J=8.54Hz, 1H) 7.70 (s, 1H) 7.75 (d, J=8.05 Hz, 1H) 8.24 (d, J=7.93 Hz, 1H)11.04 (s, 1H) 12.80 (s, 1H)

Operating in a way analogous to that described above, the followingcompound was obtained:

N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-3,5-difluoropyridine-2-carboxamide

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 4.07 (s, 2H) 6.93-6.99 (m, 2H)6.99-7.06 (m, 1H) 7.28 (dd, J=8.66, 1.46 Hz, 1H) 7.45 (d, J=8.41 Hz, 1H)7.68 (s, 1H) 8.12-8.23 (m, 1H) 8.68 (s, 1H) 10.78 (s, 1H) 12.81 (s, 1H)

Preparation of6-chloro-N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-2-(tetrahydro-2H-pyran-4-ylamino)pyridine-3-carboxamide

A solution of2,6-dichloro-N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]pyridine-3-carboxamide(80 mg, 0.18 mmol) in dioxane (1 mL) was heated at 100° C. for 24 hoursin the presence of DIPEA (0.1 mL, 0.55 mmol) andtetrahydro-2H-pyran-4-amine. (28 mg, 0.28 mmol) Reaction mixture wasdiluted with EtOAc and washed with water. The organic layer was driedover sodium sulfate, filtered and evaporated. The crude was purified byflash chromatography on silica gel using DCM/EtOH 95:5 as the eluant,affording 57 mg of the title compound.

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 1.37-1.52 (m, 2H) 1.94 (dd, J=13.05,2.80 Hz, 2H) 3.47 (td, J=11.16, 2.19 Hz, 2H) 3.80-3.87 (m, 2H) 4.06 (s,2H) 4.07-4.15 (m, 1H) 6.73 (d, J=8.05 Hz, 1H) 6.93-7.07 (m, 3H) 7.28(dd, J=8.66, 1.59 Hz, 1H) 7.44 (dd, J=8.54, 0.49 Hz, 1H) 7.55 (s, 1H)8.29 (d, J=8.17 Hz, 1H) 8.60 (d, J=7.32 Hz, 1H) 10.74 (s, 1H) 12.79 (s,1H)

Operating in a way analogous to that described above, the followingcompound was obtained:

N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-5-fluoro-3-(tetrahydro-2H-pyran-4-ylamino)pyridine-2-carboxamide

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 1.34-1.52 (m, 2H) 1.95 (d, J=10.36Hz, 2H) 3.45-3.54 (m, 2H) 3.68-3.77 (m, 1H) 3.82-3.89 (m, 2H) 4.07 (s,2H) 6.97-7.05 (m, 3H) 7.28 (dd, J=8.66, 1.59 Hz, 1H) 7.37 (dd, J=12.44,2.32 Hz, 1H) 7.43 (d, J=8.54 Hz, 1H) 7.65 (s, 1H) 7.88 (d, J=2.32 Hz,1H) 8.55 (d, J=6.95 Hz, 1H) 10.46 (s, 1H) 12.76 (s, 1H)

Preparation ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-5-(4-methylpiperazin-1-yl)-3-(tetrahydro-2H-pyran-4-ylamino)pyridine-2-carboxamide[(I_(A)), R1═R2═R3═H, R=3,5-difluorophenyl,Ar=5-(4-methylpiperazin-1-yl)-3-(tetrahydro-2H-pyran-4-ylamino)pyridine]cpd. 113

A solution ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-5-fluoro-3-(tetrahydro-2H-pyran-4-ylamino)pyridine-2-carboxamide(925 mg, 1.92 mmol) and N-methylpiperazine (20 mL) was stirred at 60° C.for 48 hours. The reaction mixture was then diluted with EtOAc andwashed with NaHCO₃ sat.sol. The organic layer was dried over sodiumsulfate, filtered and evaporated. The crude was purified by flashchromatography on silica gel using DCM/EtOH/NH₃ 5N in MeOH 100:5:0.5 asthe eluant, affording 600 mg of the title compound.

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 1.34-1.47 (m, 2H) 1.92-2.00 (m, 2H)2.25 (s, 3H) 2.44-2.49 (m, 4H) 3.34-3.40 (m, 4H) 3.48-3.56 (m, 2H)3.72-3.81 (m, 1H) 3.82-3.88 (m, 2H) 4.07 (s, 2H) 6.54 (d, J=2.20 Hz, 1H)6.95-7.07 (m, 3H) 7.26 (dd, J=8.66, 1.59 Hz, 1H) 7.41 (d, J=8.54 Hz, 1H)7.72 (s, 1H) 7.73 (d, J=2.32 Hz, 1H) 8.32 (d, J=8.05 Hz, 1H) 10.19 (s,1H) 12.66 (s, 1H)

Operating in an analogous way, the following compound was obtained:

N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-6-(4-methylpiperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)pyridine-3-carboxamide[(I_(A)), R1═R2═R3═H, R=3,5-difluorophenyl,Ar=6-(4-methylpiperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)pyridine]cpd. 114

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 1.35-1.47 (m, 2H) 1.90-2.00 (m, 2H)2.22 (s, 3H) 2.36-2.40 (m, 4H) 3.41-3.51 (m, 2H) 3.57-3.63 (m, 4H)3.78-3.88 (m, 2H) 4.05 (s, 2H) 4.06-4.11 (m, 1H) 6.10 (d, J=8.90 Hz, 1H)6.96-7.05 (m, 3H) 7.25 (dd, J=8.66, 1.59 Hz, 1H) 7.41 (d, J=8.66 Hz, 1H)7.50 (s, 1H) 8.10 (d, J=9.02 Hz, 1H) 8.73 (d, J=6.95 Hz, 1H) 10.06 (s,1H) 12.63 (s, 1H).

Example 20 Step v Preparation of tert-butyl4-[4-{[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]carbamoyl}-3-(tetrahydro-2H-pyran-4-ylamino)phenyl]piperazine-1-carboxylate

To a solution ofN-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-piperazin-1-yl-2-(tetrahydro-pyran-4-ylamino)-benzamide(71.7 mg, 0.131 mmol) in anhydrous dichloromethane (3.0 mL) andtriethylamine (0.052 mL, 38.1 mg, 0.377 mmol) di-tert-butyl-dicarbonate(34.5 mg, 0.157 mmol) was added, and the solution was stirred at roomtemperature for 40 minutes. The mixture was evaporated to dryness andpurified by flash chromatography on silica gel eluting withdichloromethane/methanol 9:1. affording 60 mg of title compound.

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 1.28-1.41 (m, 2H) 1.44 (s, 9H)1.90-1.99 (m, 2H) 3.24-3.30 (m, 4H) 3.46 (d, J=4.88 Hz, 4H) 3.48-3.54(m, 2H) 3.64-3.74 (m, 1H) 3.79-3.86 (m, 2H) 4.05 (s, 2H) 6.16 (d, J=2.19Hz, 1H) 6.25 (dd, J=8.90, 2.19 Hz, 1H) 6.95-7.04 (m, 3H) 7.26 (dd,J=8.66, 1.46 Hz, 1H) 7.41 (d, J=8.90 Hz, 1H) 7.49 (s, 1H) 7.82 (d,J=9.15 Hz, 1H) 8.29 (d, J=7.44 Hz, 1H) 10.10 (s, 1H) 12.64 (s, 1H)

Preparation of ethyl5-(3,5-difluorobenzyl)-3-({[4-(piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)phenyl]carbonyl}amino)-1H-indazole-1-carboxylate

To a solution of tert-butyl4-[4-{[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]carbamoyl}-3-(tetrahydro-2H-pyran-4-ylamino)phenyl]piperazine-1-carboxylate(0.013 mmol) in anhydrous tetrahydrofurane (1.0 mL) maintained at −50°C. under argon atmosphere a 1M solution of LiHMSD in anhydroustetrahydrofurane (0.015 mL) was added. After stirring at thattemperature for 5 minutes ethyl chlorocarbonate (0.002 mL, 1.63 mg,0.015 mmol) was added. After 30 minutes at −50° C. the reaction wascompleted. After diluting with dichloromethane, the solution was washedwith brine, dried over sodium sulphate and evaporated to dryness. Thecrude was dissolved in dichloromethane (1 mL), trifluoroacetic acid (0.1mL) was added and the mixture was stirred at room temperature overnight.After diluting with dichloromethane, the solution was washed with sodiumhydrogencarbonate, with brine, dried over sodium sulphate and evaporatedto dryness.

The crude was purified by flash chromatography on silica gel elutingwith dichloromethane/methanol 9:1 and a 0.5% of aq. 33% NH₄OH affordingthe title compound.

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 1.30-1.38 (m, 2H) 1.40 (t, J=7.13Hz, 3H) 1.90-1.99 (m, 2H) 2.79-2.86 (m, 4H) 3.18-3.23 (m, 4H) 3.47-3.54(m, 2H) 3.63-3.76 (m, 1H) 3.79-3.86 (m, 2H) 4.11 (s, 2H) 4.48 (q, J=7.15Hz, 2H) 6.11 (d, J=2.07 Hz, 1H) 6.24 (dd, J=9.15, 2.19 Hz, 1H) 6.97-7.07(m, 3H) 7.55 (dd, J=8.66, 1.59 Hz, 1H) 7.67 (d, J=0.73 Hz, 1H) 7.80 (d,J=9.02 Hz, 1H) 8.07 (d, J=8.66 Hz, 1H) 8.24 (d, J=7.56 Hz, 1H) 10.65(br. s., 1H)

Preparation of 1-(acetyloxy)ethyl4-[4-{[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]carbamoyl}-3-(tetrahydro-2H-pyran-4-ylamino)phenyl]piperazine-1-carboxylate

To a solution ofN-[5-(3,5-Difluoro-benzyl)-1H-indazol-3-yl]-4-piperazin-1-yl-2-(tetrahydro-pyran-4-ylamino)-benzamidein chloroform (5.0 mL), cooled to 0° C. under nitrogen,1,8-bis(dimethylamino)naphtalene (21.4 mg, 0.1 mmol) and(1-chloroethyl)chloroformate (0.011 mL, 14.3 mg, 0.1 mmol) were added.After stirring for 2 hours at room temperature the mixture was dilutedwith dichloromethane (30 mL), washed with saturated sodiumhydrogencarbonate solution (3 mL), brine (3×5 mL), dried over sodiumsulphate and evaporated to dryness. The crude was dissolved in glacialacetic acid (2.0 mL), mercury (II) acetate (31.9 mg, 0.1 mmol) was addedand the mixture was stirred at room temperature for 1.5 hours. Afterremoving the solvent, the crude was taken up with dichloromethane,washed with saturated sodium hydrogencarbonate solution (3×3 mL), brine(3×5 mL), dried over sodium sulphate and evaporated to dryness to yield50 mg of yellowish foam that was purified by flash chromatography onsilica gel eluting with ethyl acetate and a 0.5% of aq. 33% NH₄OHaffording 35 mg of the title compound.

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 1.29-1.42 (m, 2H) 1.46 (d, J=5.49Hz, 3H) 1.90-1.98 (m, 2H) 2.03-2.06 (m, 3H) 3.30-3.50 (m, 8H) 3.45-3.52(m, 2H) 3.64-3.74 (m, 1H) 3.79-3.86 (m, 2H) 4.05 (s, 2H) 6.16 (d, J=2.07Hz, 1H) 6.25 (dd, J=9.02, 2.07 Hz, 1H) 6.67-6.73 (m, 1H) 6.94-7.05 (m,3H) 7.26 (dd, J=8.66, 1.59 Hz, 1H) 7.41 (d, J=8.66 Hz, 1H) 7.49 (s, 1H)7.82 (d, J=9.02 Hz, 1H) 8.30 (d, J=7.68 Hz, 1H) 10.11 (s, 1H) 12.64 (s,1H)

Preparation of ethyl5-(3,5-difluorobenzyl)-3-({[4-(4-methylpiperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)phenyl]carbonyl}amino)-1H-indazole-1-carboxylate[(XXVII), R1═R2═R3═H, R=3,5-difluorophenyl,Ar=4-(4-methylpiperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)phenyl,PG=ethoxycarbonyl] cpd. 140

To a solution ofN-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide(200 mg, 0.356 mmol) in anhydrous tetrahydrofurane (9 mL) maintained at−50° C. under nitrogen atmosphere a 1M solution of LiHMSD in anhydroustetrahydrofurane (0.374 mL) was added. After stirring at thattemperature for 5 minutes ethyl chloroformate (0.036 mL, 0.374 mmol) wasadded. After 1 hour at −50° C. the reaction was completed. Reactionmixture was diluted with water/EtOAc, washed with brine, dried oversodium sulphate and evaporated to dryness. The crude was purified byflash chromatography on silica gel eluting with DCM/ethanol 100:5,affording 140 mg (62% yield) of the title compound.

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 1.39 (t, J=7.07 Hz, 3H) 2.25 (br.s., 3H) 2.46 (br. s., 4H) 3.50 (ddd, J=11.83, 10.06, 2.26 Hz, 1H)3.66-3.75 (m, 1H) 3.81 (dt, J=11.61, 3.76 Hz, 2H) 4.10 (s, 2H) 4.47 (q,J=7.15 Hz, 2H) 6.13 (d, J=1.95 Hz, 1H) 6.25 (dd, J=9.08, 2.13 Hz, 1H)7.54 (dd, J=8.66, 1.59 Hz, 1H) 7.66 (dd, J=1.46, 0.73 Hz, 1H) 7.80 (d,J=9.15 Hz, 1H) 8.07 (d, J=8.66 Hz, 1H) 8.24 (d, J=7.68 Hz, 1H) 10.65 (s,1H)

Operating in a way analogous to that described above, the followingcompounds were obtained:

2-methoxyethyl5-(3,5-difluorobenzyl)-3-({[4-(4-methylpiperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)phenyl]carbonyl}amino)-1H-indazole-1-carboxylate

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 1.30-1.43 (m, 2H) 1.90-2.00 (m, 2H)2.26 (br. s., 3H) 2.47 (br. s., 4H) 3.27-3.33 (m, 7H) 3.46-3.55 (m, 2H)3.67-3.74 (m, 3H) 3.79-3.85 (m, 2H) 4.11 (s, 2H) 4.54-4.59 (m, 2H) 6.14(d, J=1.71 Hz, 1H) 6.26 (dd, J=9.02, 2.19 Hz, 1H) 6.97-7.09 (m, 3H) 7.56(dd, J=8.72, 1.52 Hz, 1H) 7.67 (d, J=0.85 Hz, 1H) 7.81 (d, J=9.15 Hz,1H) 8.07 (d, J=8.54 Hz, 1H) 8.25 (d, J=7.56 Hz, 1H) 10.68 (s, 1H)

ethyl5-(3,5-difluorobenzyl)-3-[({4-[4-(ethoxycarbonyl)piperazin-1-yl]-2-(tetrahydro-2H-pyran-4-ylamino)phenyl}carbonyl)amino]-1H-indazole-1-carboxylate

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 1.22 (t, J=7.07 Hz, 3H) 1.30-1.38(m, 2H) 1.40 (t, J=7.07 Hz, 3H) 1.90-2.00 (m, 2H) 3.48-3.54 (m, 2H) 3.71(d, 1H) 3.78-3.86 (m, 2H) 4.05-4.10 (m, 2H) 4.11 (s, 2H) 4.48 (q, J=7.03Hz, 2H) 6.15 (d, J=2.07 Hz, 1H) 6.26 (dd, J=9.15, 2.19 Hz, 1H) 6.95-7.07(m, 2H) 7.55 (dd, J=8.66, 1.59 Hz, 1H) 7.67 (d, J=0.85 Hz, 1H) 7.83 (d,J=9.15 Hz, 1H) 8.08 (d, J=8.78 Hz, 1H) 8.25 (d, J=7.80 Hz, 1H) 10.68 (s,1H)

Example 21 Preparation of 4-fluoro-2-nitro-benzoic acid tert-butyl ester

A solution of 4-fluoro-2-nitro benzoic acid (10 g, 54 mmol), (Boc)₂O (2eq., 23.6 g, 108 mmol) and 4-(N,N-dimethylamino)pyridine (0.3 eq., 1.98g, 16.2 mmol) in tert-butanol (100 mL) and dichloromethane (100 mL) wasstirred at room temperature for 20 hours. The reaction mixture was thendiluted with ethyl acetate (500 mL), washed with 1N HCl (500 mL), water(500 mL), brine (500 mL), dried over sodium sulfate and evaporated todryness. The title compound was obtained as pale yellow oil(quantitative) and it was used in the next step without any furtherpurification.

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 8.04 (dd, J=8.47, 2.50 Hz, 1H) 7.95(dd, J=8.66, 5.37 Hz, 1H) 7.71 (ddd, J=8.66, 8.17, 2.56 Hz, 1H) 1.51 (s,9H).

Preparation of 4-(4-methyl-piperazin-1-yl)-2-nitro-benzoic acidtert-butyl ester

A solution of 4-fluoro-2-nitro-benzoic acid tert-butyl ester (13 g, 54mmol) and N-methylpiperazine (17 mL) was stirred at room temperature for6 hours. The reaction mixture was then diluted with water (800 mL) andmaintained under magnetic stirring for 20 hours. The resulting solid wasfiltered, washed thoroughly with water and dried under vacuum at 40° C.The title compound was obtained as yellow solid (16.4 g, 94% yield) andit was used in the next step without any further purification.

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 7.69 (d, J=8.90 Hz, 1H) 7.29 (d,J=2.56 Hz, 1H), 7.15 (dd, J1=8.90 Hz, J2=2.56 Hz, 1H), 3.37 (m, 4H),2.44 (m, 4H), 1.46 (s, 9H).

Operating in an analogous way, the following compounds were obtained:

4-[(2-Dimethylamino-ethyl)-methyl-amino]-2-nitro-benzoic acid tert-butylester

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 7.67 (d, J=8.9 Hz, 1H), 6.98 (d,J=2.6 Hz, 1H), 6.89 (dd, J1=8.9 Hz, J2=2.6 Hz, 1H), 3.54 (m, 2H), 3.02(s, 3H), 2.40 (m, 2H), 2.19 (s, 6H), 1.46 (s, 9H).

4-(4-Dimethylamino-piperidin-1-yl)-2-nitro-benzoic acid tert-butyl ester

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 7.67 (d, J=9.0 Hz, 1H), 7.26 (d,J=2.6 Hz, 1H), 7.13 (dd, J1=9.0 Hz, J2=2.6 Hz, 1H), 3.96 (m, 2H), 2.93(m, 2H), 2.36 (m, 1H), 2.20 (s, 6H), 1.82 (m, 2H), 1.46 (s, 9H), 1.40(m, 2H).

4-[(3-Dimethylamino-propyl)-methyl-amino]-2-nitro-benzoic acidtert-butyl ester

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 7.67 (d, J=9.0 Hz, 1H), 7.02 (d,J=2.6 Hz, 1H), 6.90 (dd, J1=9.0 Hz, J2=2.6 Hz, 1H), 3.46 (m, 2H), 3.00(s, 3H), 2.22 (m, 2H), 2.14 (s, 6H), 1.65 (m, 2H), 1.45 (s, 9H).

tert-butyl 4-(4-methyl-1,4-diazepan-1-yl)-2-nitrobenzoate

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 1.44 (s, 9H) 1.85 (m, 2H) 2.25 (s,3H) 2.43 (m, 2H) 2.60 (m, 21) 3.51 (t, 2H) 3.60 (t, 2H) 6.91 (dd,J1=9.02 Hz, J2=2.66 Hz, 1H) 7.02 (d, J=2.56 Hz, 1H) 7.64 (d, J=8.90 Hz,1H) tert-butyl 2-nitro-4-(piperazin-1-yl)benzoate

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 1.46 (m, 9H) 2.81 (m, 4H) 3.33 (m,4H) 7.12 (dd, J1=8.90 Hz, J2=2.56 Hz, 1H) 7.25 (d, J=2.56 Hz, 1H) 7.65(d, J=8.90 Hz, 1H)

tert-butyl2-nitro-4-[(2S)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]benzoate

ESI(+) MS: m/z 376 (MH⁺).

Preparation of 2-amino-4-(4-methyl-piperazin-1-yl)-benzoic acidtert-butyl ester

A mixture of 4-(4-methyl-piperazin-1-yl)-2-nitro-benzoic acid tert-butylester (13.3 g, 41.5 mmol) cyclohexene (45 mL), ethanol (300 mL) and 10%Pd/C (0.4 g) was stirred at 80° C. for 7 hours. More 10% Pd/C was added(0.9 g) and the mixture stirred at 80° C. for additional 4 hours. Thereaction mixture was filtered over a celite pad washing thoroughly withethanol and the filtrate was evaporated to dryness affording the titlecompound as a pale yellow solid (11.5 g, 95% yield).

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 7.47 (d, J=9.0 Hz, 1H), 6.40 (bs,2H), 6.18 (dd, J1=9.0 Hz, J2=2.4 Hz, 1H), 6.11 (d, J=2.4 Hz, 1H), 3.16(m, 4H), 2.41 (m, 4H), 2.21 (s, 3H), 1.49 (s, 9H).

Operating in an analogous way, the following compounds were obtained:

2-Amino-4-[(2-dimethylamino-ehtyl)-methyl-amino]-benzoic acid tert-butylester

ESI(+) MS: m/z 294 (MH⁺).

2-Amino-4-[(3-dimethylamino-propyl)-methyl-amino]-benzoic acidtert-butyl ester

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 7.45 (d, J=9.0 Hz, 1H), 6.36 (bs,2H), 5.99 (dd, J1=9.0 Hz, J2=2.6 Hz, 1H), 5.86 (d, J=2.6 Hz, 1H), 3.31(m, 2H), 2.87 (s, 3H), 2.22 (m, 2H), 2.15 (s, 6H), 1.62 (m, 2H), 1.48(s, 9H).

tert-butyl 2-amino-4-[4-(trifluoroacetyl)piperazin-1-yl]benzoate

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 1.51 (s, 9H) 3.28-3.35 (m, 4H)3.66-3.74 (m, 4H) 6.15 (d, J=2.44 Hz, 1H) 6.21 (dd, J=9.14, 2.44 Hz, 1H)6.47 (br. s., 2H) 7.50-7.53 (m, 1H)

tert-butyl 2-amino-4-[4-(dimethylamino)piperidin-1-yl]benzoate

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 1.31-1.45 (m, 2H) 1.49-1.52 (m, 9H)1.75-1.81 (m, 2H) 2.17 (s, 6H) 2.20-2.30 (m, 1H) 2.69-2.79 (m, 2H)3.71-3.80 (m, 2H) 6.12 (d, J=2.44 Hz, 1H) 6.18 (dd, J=9.14, 2.44 Hz, 1H)6.39 (s, 2H) 7.46 (d, J=9.02 Hz, 1H)

tert-butyl 2-amino-4-(4-methyl-1,4-diazepan-1-yl)benzoate

ESI(+) MS: m/z 306 (MH⁺).

tert-butyl2-amino-4-[(2S)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]benzoate

ESI(+) MS: m/z 346 (MH⁺).

tert-butyl 2-amino-4-(morpholin-4-yl)benzoate

ESI(+) MS: m/z 279 (MH⁺).

Preparation of4-(4-methyl-piperazin-1-yl)-2-tetrahydro-pyran-4-ylamino)-benzoic acidtert-butyl ester

To a solution of 2-amino-4-(4-methyl-piperazin-1-yl)-benzoic acidtert-butyl ester (11.5 g, 39.5 mmol) in dichloromethane (340 mL) wereadded tetrahydro-pyran-4-one (4.5 mL, 49.3 mmol), trifluoroacetic acid(8.2 mL) and tetramethylammonium triacetoxyborohydride (15.57 g, 59.2mmol). The mixture was stirred at room temperature for 2 hours thenwashed with 0.5N hydrochloric acid, with 0.5N NaOH and with a saturatedsolution of NaHCO₃. The organic layer was dried over sodium sulfate andevaporated to dryness affording the title compound as a pale yellowsolid (13.3 g, 90% yield).

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 7.72 (d, J=7.7 Hz, 1H), 7.58 (d,J=9.1 Hz, 1H), 6.20 (dd, J1=9.1 Hz, J2=2.2 Hz, 1H), 6.08 (d, J=2.2 Hz,1H), 3.85 (m, 2H), 3.70 (m, 1H), 3.50 (m, 2H), 3.27 (m, 4H), 2.47 (m,4H), 2.26 (bt, 3H), 1.96 (m, 2H), 1.51 (s, 9H), 1.39 (m, 2H).

Operating in an analogous way, the following compounds were obtained:

4-[(2-Dimethylamino-ethyl)-methyl-amino]-2-(tetrahydro-pyran-4-ylamino)-benzoicacid tert-butyl ester

ESI(+) MS: m/z 378 (MH⁺).

4-[(3-Dimethylamino-propyl)-methyl-amino]-2-(tetrahydro-pyran-4-ylamino)-benzoicacid tert-butyl ester

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 7.70 (bd, J=7.4 Hz, 1H), 7.54 (d,J=9.0 Hz, 1H), 5.99 (dd, J1=9.0 Hz, J2=2.3 Hz, 1H), 5.79 (d, J=2.3 Hz,1H), 3.86 (m, 2H), 3.62 (m, 1H), 3.47 (m, 2H), 3.36 (m, 2H), 2.93 (s,3H), 2.28 (m, 2H), 2.18 (bs, 6H), 1.97 (m, 2H), 1.64 (m, 2H), 1.49 (s,9H), 1.39 (m, 2H).

tert-butyl2-(tetrahydro-2H-pyran-4-ylamino)-4-[4-(trifluoroacetyl)piperazin-1-yl]benzoate

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 1.33-1.45 (m, 2H) 1.51 (s, 9H)1.92-2.00 (m, 2H) 3.36-3.42 (m, 4H) 3.50 (td, J=11.18, 2.13 Hz, 2H) 3.70(d, J=3.05 Hz, 5H) 3.82-3.89 (m, 2H) 6.10 (d, J=2.32 Hz, 1H) 6.21 (dd,J=9.08, 2.26 Hz, 1H) 7.61 (d, J=9.02 Hz, 1H) 7.73 (d, J=7.68 Hz, 1H)

tert-butyl4-[4-(dimethylamino)piperidin-1-yl]-2-(tetrahydro-2H-pyran-1-ylamino)benzoate

ESI(+) MS: m/z 404 (MH⁺).

tert-butyl4-(4-methyl-1,4-diazepan-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzoate

ESI(+) MS: m/z 390 (MH⁺).

tert-butyl4-[(2S)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]-2-(tetrahydro-2H-pyran-4-ylamino)benzoate

ESI(+) MS: m/z 430 (MH⁺).

tert-butyl 2-(cyclobexylamino)-4-(4-methylpiperazin-1-yl)benzoate

ESI(+) MS: m/z 374 (MH⁺).

tert-butyl2-[(1,3-dimethoxypropan-2-yl)amino]-4-(4-methylpiperazin-1-yl)benzoate

ESI(+) MS: m/z 394 (MH⁺).

tert-butyl 2-(benzylamino)-4-(4-methylpiperazin-1-yl)benzoate

ESI(+) MS: m/z 382 (MH⁺).

tert-butyl4-(4-methylpiperazin-1-yl)-2-{[cis-4-(trifluoromethyl)cyclohexyl]amino}benzoate

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 1.40-1.50 (m, 2H) 1.51 (s, 9H)1.57-1.69 (m, 2H) 1.70-1.78 (m, 2H) 1.87 (d, J=14.27 Hz, 2H) 2.24 (s,3H) 2.32-2.39 (m, 1H) 2.40-2.48 (m, 4H) 3.27 (br. s., 4H) 3.83-3.94 (m,1H) 6.05 (d, J=1.95 Hz, 1H) 6.20 (dd, J=9.21, 2.26 Hz, 1H) 7.57 (d,J=9.02 Hz, 1H) 8.04 (d, J=8.05 Hz, 1H)

tert-butyl4-(4-methylpiperazin-1-yl)-2-{[trans-4-(trifluoromethyl)cyclohexyl]amino}benzoate

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 1.18-1.31 (m, 2H) 1.44-1.57 (m, 2H)1.50 (s, 9H) 1.87-1.94 (m, 2H) 2.07-2.13 (m, 2H) 2.25 (s, 3H) 2.28-2.38(m, 1H) 2.44 (br. s., 4H) 3.26 (br. s., 4H) 3.40-3.53 (m, 1H) 6.07 (d,J=2.07 Hz, 1H) 6.18 (dd, J=9.08, 2.26 Hz, 1H) 7.54-7.58 (m, 1H) 7.62 (d,J=7.93 Hz, 1H)

tert-butyl4-(4-methylpiperazin-1-yl)-2-({cis-4-[(phenylcarbonyl)oxy]cyclohexyl}amino)benzoate

ESI(+) MS: m/z 494 (MH⁺).

tert-butyl4-(4-methylpiperazin-1-yl)-2-({trans-4-[(phenylcarbonyl)oxy]cyclohexyl}amino)benzoate

ESI(+) MS: m/z 494 (MH⁺).

tert-butyl 2-[(1-methylpiperidin-4-yl)amino]benzoate

ESI(+) MS: m/z 291 (MH⁺).

tert-butyl 2-[(1-methylpiperidin-4-yl)amino]-4-(morpholin-4-yl)benzoate

ESI(+) MS: m/z 376 (MH⁺).

Preparation of4-(4-methyl-piperazin-1-yl)-2-[(tetrahydro-pyran-4-yl)-(2,2,2-trifluoro-acetyl)-amino]-benzoicacid tert-butyl ester

To a solution of4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzoic acidtert-butyl ester (13.3 g, 35.4 mmol) in dry dichloromethane (350 mL),under argon, at 0° C., were added triethylamine (7.5 mL, 53.1 mmol) andtrifluoroacetic anhydride (6.5 mL, 46.1 mmol). The mixture was stirredat 0° C. for 20 minutes, then water (350 mL) was dropped. The phaseswere separated and the organic phase washed with brine, dried oversodium sulfate and evaporated to dryness. The crude residue was purifiedby chromatography on silica gel using dichloromethane/ethanol 95:5 asthe eluant, affording 12.1 g of the title compound as a pale yellowsolid (73% yield).

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 7.83 (d, J=9.0 Hz, 1H), 7.06 (dd,J1=9.0 Hz, J2=2.5 Hz, 1H), 6.82 (J=2.5 Hz, 1H), 4.48 (m, 1H), 3.85 (m,2H), 3.5-3.3 (m, 6H), 2.49 (m, 4H), 2.26 (bs, 3H), 2.0 (m, 1H), 1.59 (m,1H), 1.51 (m, 1H), 1.46 (s, 9H), 1.03 (m, 1H).

Operating in an analogous way, the following compounds were obtained:

4-[(2-Dimethylamino-ethyl)-methyl-amino]-2-[(tetrahydro-pyran-4-yl)-(2,2,2-trifluoro-acetyl)-amino]-benzoicacid tert-butyl ester

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 7.80 (d, J=9.1 Hz, 1H), 6.79 (dd,J1=9.1 Hz, J2=2.6 Hz, 1H), 6.51 (d, J=2.6 Hz, 1H), 4.48 (m, 1H), 3.86(m, 1H), 3.79 (m, 1H), 3.52 (m, 2H), 3.41-3.25 (m, 2H), 3.00 (s, 3H),2.5-2.35 (m, 2H), 2.21 (s, 6H), 1.98 (m, 1H), 1.64-1.45 (m, 3H), 1.44(s, 9H).

4-[(3-Dimethylamino-propyl)-methyl-amino]-2-[(tetrahydro-pyran-4-yl)-(2,2,2-trifluoro-acetyl)-amino]-benzoicacid tert-butyl ester

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 7.79 (d, J=9.1 Hz, 1H), 6.79 (dd,J1=9.1 Hz, J2=2.6 Hz, 1H), 6.52 (d, J=2.6 Hz, 1H), 4.48 (m, 1H), 3.87(m, 1H), 3.79 (m, 1H), 3.51-3.32 (m, 4H), 2.98 (s, 3H), 2.22 (m, 2H),2.12 (s, 6H), 1.99 (m, 1H), 1.70-1.46 (m, 4H), 1.44 (s, 9H), 1.03 (m,1H).

tert-butyl2-[tetrahydro-2H-pyran-4-yl(trifluoroacetyl)amino]-4-[4-(trifluoroacetyl)piperazin-1-yl]benzoate

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 1.45 (s, 9H) 1.60 (qd, J=12.21, 4.94Hz, 2H) 3.73 (t, J=5.12 Hz, 4H) 4.48 (tt, J=11.96, 3.89 Hz, 1H) 6.84 (d,J=2.56 Hz, 1H) 7.07 (dd, J=8.96, 2.62 Hz, 1H) 7.85 (d, J=9.02 Hz, 1H)

tert-butyl4-[4-(dimethylamino)piperidin-1-yl]-2-[tetrahydro-2H-pyran-4-yl(trifluoroacetyl)amino]benzoate

ESI(+) MS: m/z 500 (MH⁺).

tert-butyl4-(4-methyl-1,4-diazepan-1-yl)-2-[tetrahydro-2H-pyran-4-yl(trifluoroacetyl)amino]benzoate

ESI(+) MS: m/z 486 (MH⁺).

tert-butyl4-[(2S)-2-(pyrrolin-1-ylmethyl)pyrrolin-1-yl]-2-[tetrahydro-2H-pyran-4-yl(trifluoroacetyl)amino]benzoate

ESI(+) MS: m/z 526 (MH⁺).

tert-butyl2-[cyclohexyl(trifluoroacetyl)amino]-4-(4-methylpiperazin-1-yl)benzoate

ESI(+) MS: m/z 470 (MH⁺).

tert-butyl2-[(1,3-dimethoxypropan-2-yl)(trifluoroacetyl)amino]-4-(4-methylpiperazin-1-yl)benzoate

ESI(+) MS: m/z 490 (MH⁺).

tert-butyl2-[benzyl(trifluoroacetyl)amino]-4-(4-methylpiperazin-1-yl)benzoate

ESI(+) MS: m/z 478 (MH⁺).

tert-butyl 4-(4-methylpiperazin-1-yl)-2-{(trifluoroacetyl)[cis-4-(trifluoromethyl)cyclohexyl]amino}benzoate

ESI(+) MS: m/z 538 (MH⁺).

tert-butyl 4-(4-methylpiperazin-1-yl)-2-{(trifluoroacetyl)[trans-4-(trifluoromethyl)cyclohexyl]amino}benzoate

ESI(+) MS: m/z 538 (MH⁺).

tert-butyl4-(4-methylpiperazin-1-yl)-2-[{cis-4-[(phenylcarbonyl)oxy]cyclohexyl}(trifluoroacetyl)amino]benzoate

ESI(+) MS: m/z 590 (MH⁺).

tert-butyl4-(4-methylpiperazin-1-yl)-2-[{trans-4-[(phenylcarbonyl)oxy]cyclohexyl}(trifluoroacetyl)amino]benzoate

ESI(+) MS: m/z 590 (MH⁺).

tert-butyl 2-[(1-methylpiperidin-4-yl)(trifluoroacetyl)amino]benzoate

ESI(+) MS: m/z 387 (MH⁺).

tert-butyl2-[(1-methylpiperidin-4-yl)(trifluoroacetyl)amino]-4-(morpholin-4-yl)benzoate

ESI(+) MS: m/z 472 (MH⁺).

tert-butyl4-(4-methylpiperazin-1-yl)-2-[phenyl(trifluoroacetyl)amino]benzoate

ESI(+) MS: m/z 464 (MH⁺).

Preparation of4-(4-methyl-piperazin-1-yl)-2-[(tetrahydro-pyran-4-yl)-(2,2,2-trifluoro-acetyl)-amino]-benzoicacid trifluoroacetate

A mixture of4-(4-methyl-piperazin-1-yl)-2-[(tetrahydro-pyran-4-yl)-(2,2,2-trifluoro-acetyl)-amino]-benzoicacid tert-butyl ester (12.1 g, 25.7 mmol), trifluoroacetic acid (48.5mL) and dichloromethane (195 mL) was stirred at room temperature for 2hours. The volatiles were then evaporated, the residue taken up withdiethylether and evaporated again. The procedure was repeated for 5times, then the solid was triturated with diethylether, filtered anddried in oven at 40° C. affording the title compound as a pale brownsolid (13.4 g).

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.78 (bs, 1H), 9.74 (bs, 1H), 7.93(d, J=8.8 Hz, 1H), 7.13 (dd, J1=8.8 Hz, J2=2.5 Hz, 1H), 6.98 (d, J=2.5Hz, 1H), 4.49 (m, 1H), 4.11 (m, 2H), 3.84 (m, 2H), 3.6-3.0 (m, 8H), 2.89(s, 3H), 1.98 (m, 1H), 1.59 (m, 1H), 1.53 (m, 1H), 1.08 (m, 1H).

Operating in an analogous way, the following compounds were obtained:

4-[(2-Dimethylamino-ethyl)-methyl-amino]-2-[(tetrahydro-pyran-4-yl)-(2,2,2-trifluoro-acetyl)-amino]-benzoicacid trifluoroacetate

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.56 (bs, 1H), 9.49 (bs, 1H), 7.88(d, J=8.9 Hz, 1H), 8.92 (dd, J1=8.9 Hz, J2=2.6 Hz, 1H), 6.63 (d, J=2.6Hz, 1H), 4.49 (m, 1H), 3.9-3.2 (m, 8H), 3.02 (s, 3H), 2.85 (s, 6H), 1.98(m, 1H), 1.62-1.49 (m, 2H), 1.08 (m, 1H).

4-[(3-Dimethylamino-propyl)-methyl-amino]-2-[(tetrahydro-pyran-4-yl)-(2,2,2-trifluoro-acetyl)-amino]-benzoicacid trifluoroacetate

ESI(+) MS: m/z 432 (MH⁺).

2-[tetrahydro-2H-pyran-4-yl(trifluoroacetyl)amino]-4-[4-(trifluoroacetyl)piperazin-1-yl]benzoicacid

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 1.08 (m, J=12.35, 12.24, 12.24, 4.76Hz, 1H) 1.47-1.55 (m, 1H) 1.56-1.67 (m, 1H) 1.91-2.01 (m, 1H) 3.38-3.53(m) 3.73 (t, J=5.12 Hz, 4H) 3.78 (dd, J=11.52, 4.45 Hz, 1H) 3.86 (dd,J=11.40, 4.57 Hz, 1H) 4.46 (tt, J=11.87, 3.98 Hz, 1H) 6.85 (d, 1H) 7.06(dd, J=8.90, 2.68 Hz, 1H) 7.89 (d, J=8.90 Hz, 1H) 12.67 (br. s., 1H)

4-(4-methyl-1,4-diazepan-1-yl)-2-[tetrahydro-2H-pyran-4-yl(trifluoroacetyl)amino]benzoicacid hydrochloride

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 4.42-4.55 (m, 1H) 6.91-6.96 (m, 1H)7.89 (d, J=9.02 Hz, 1H) 10.14 (br. s., 1H) 12.56 (br. s., 1H)

4-[4-(dimethylamino)piperidin-1-yl]-2-[tetrahydro-2H-pyran-4-yl(trifluoroacetyl)amino]benzoicacid hydrochloride

ESI(+) MS: m/z 444 (MH⁺).

4-[(2S)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]-2-[tetrahydro-2H-pyran-4-yl(trifluoroacetyl)amino]benzoicacid hydrochloride

ESI(+) MS: m/z 470 (MH⁺).

2-[cyclohexyl(trifluoroacetyl)amino]-4-(4-methylpiperazin-1-yl)benzoicacid hydrochloride

ESI(+) MS: m/z 414 (MH⁺).

2-[(1,3-dimethoxypropan-2-yl)(trifluoroacetyl)amino]-4-(4-methylpiperazin-1-yl)benzoicacid hydrochloride

ESI(+) MS: m/z 434 (MH⁺).

2-[benzyl(trifluoroacetyl)amino]-4-(4-methylpiperazin-1-yl)benzoic acidhydrochloride

ESI(+) MS: m/z 422 (MH⁺).

4-(4-methylpiperazin-1-yl)-2-{(trifluoroacetyl)[cis-4-(trifluoromethyl)cyclohexyl]amino}benzoicacid trifluoroacetate

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 1.09-1.90 (4m, 8H) 2.36-2.46 (m, 1H)2.88 (br. s., 3H) 2.99-3.25 (m, 4H) 3.49 (br. s., 2H) 3.96-4.16 (m, 2H)4.27-4.37 (m, 1H) 7.00 (d, J=2.32 Hz, 1H) 7.12 (dd, J=8.90, 2.44 Hz, 1H)7.92 (d, J=8.90 Hz, 1H) 9.67 (br. s., 1H) 12.80 (s, 1H)

4-(4-methylpiperazin-1-yl)-2-{(trifluoroacetyl)[trans-4-(trifluoromethyl)cyclohexyl]amino}benzoicacid trifluoroacetate

ESI(+) MS: m/z 482 (MH⁺).

4-(4-methylpiperazin-1-yl)-2-[{cis-4-[(phenylcarbonyl)oxy]cyclohexyl}(trifluoroacetyl)amino]benzoicacid hydrochloride

ESI(+) MS: m/z 534 (MH⁺).

4-(4-methylpiperazin-1-yl)-2-[{trans-4-[(phenylcarbonyl)oxy]cyclobexyl}(trifluoroacetyl)amino]benzoicacid hydrochloride

ESI(+) MS: m/z 534 (MH⁺).

2-[(1-methylpiperidin-4-yl)(trifluoroacetyl)amino]benzoic acidhydrochloride

ESI(+) MS: m/z 331 (MH⁺).

2-[(1-methylpiperidin-4-yl)(trifluoroacetyl)amino]-4-(morpholin-4-yl)benzoicacid hydrochloride

ESI(+) MS: m/z 416 (MH⁺).

4-(4-methylpiperazin-1-yl)-2-[phenyl(trifluoroacetyl)amino]benzoic acidhydrochloride

ESI(+) MS: m/z 408 (MH⁺).

Example 22 Preparation of 2,4-difluoro-benzoic acid tert-butyl ester

To a solution of 2,4-difluorobenzoic acid (5 g, 31.62 mmol) in a mixtureof dichloromethane (100 mL) and t-BuOH (50 mL) were added (Boc)₂O (13.8g, 63.24 mmol) and N,N-dimethylaminopyridine (1.16 g, 9.49 mmol). Thesolution was stirred at room temperature for 24 hours then diluted withdichloromethane and washed twice with 1N HCl, NaHCO₃ satured solution,water (3 times) and brine. The organic phase was dried over sodiumsulfate, filtered and evaporated to give the title compound (5.70 g,84%) as yellowish oil.

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 7.91 (m, 1H), 7.36 (m, 1H), 7.20 (m,1H), 1.53 (s, 9H).

Preparation of 4-fluoro-2-((S)-2-methoxy-1-methyl-ethylamino)-benzoicacid tert-butyl ester

A mixture of 2,4-difluoro-benzoic acid tert-butyl ester (30 g, 140.05mmol) and (S)-2-methoxy-1-methyl-ethylamine (100 mL) was stirred at 65°C. for 2 days. A satured solution of NaHCO₃ was added and the mixturewas extracted with dichloromethane (3 times). The organic phase waswashed twice with water then with brine, dried over sodium sulfatefiltered and evaporated to dryness to obtain a crude, which was purifiedby column chromatography on silica gel (exane/ethyl acetate 9:1). Thetitle compound (33.38 g, 84%) was obtained as oil.

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 7.87 (d, J=7.80 Hz, 1H), 7.80 (t,J=7.19 Hz, 1H), 6.60 (dd, J1=13.05 Hz, J2=2.44 Hz, 1H), 6.36 (m, 1H),3.80 (m, 1H), 3.40 (d, J=4.76 Hz, 2H), 3.30 (s, 3H), 1.53 (s, 9H), 1.17(d, J=6.58 Hz, 3H).

Operating in a way analogous to that described above, the followingcompounds were obtained:

4-Fluoro-2-((R)-2-methoxy-1-methyl-ethylamino)-benzoic add tert-butylester

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 7.87 (d, J=7.80 Hz, 1H), 7.80 (t,J=7.19 Hz, 1H), 6.60 (dd, J1=13.05 Hz, J2=2.44 Hz, 1H), 6.36 (m, 1H),3.80 (m, 1H), 3.40 (d, J=4.76 Hz, 2H), 3.30 (s, 3H), 1.53 (s, 9H), 1.17(d, J=6.58 Hz, 3H).

4-Fluoro-2-(2-methoxy-ethylamino)-benzoic acid tert-butyl ester

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 7.89 (t, J=5.00 Hz, 1H), 7.80 (t,J=7.07 Hz, 1H), 6.56 (dd, J1=12.80 Hz, J2=2.56 Hz, 1H), 6.37 (m, 1H),3.55 (t, J=5.37 Hz, 2H), 3.33 (m, 2H), 3.29 (s, 3H), 1.53 (s, 9H).

tert-butyl 4-fluoro-2-[(3-methoxypropyl)amino]benzoate

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 1.51-1.53 (m, 9H) 1.76-1.85 (m, 2H)3.18-3.23 (m, 2H) 3.25 (s, 3H) 3.38-3.44 (m, 2H) 6.32-6.39 (m, 1H) 6.49(dd, J=12.80, 2.44 Hz, 1H) 7.79 (dd, J=8.90, 7.07 Hz, 1H) 7.88 (br. s.,1H)

tert-butyl 4-fluoro-2-[(2-fluoroethyl)amino]benzoate

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 1.54 (s, 9H) 3.50 (dd, J=27.00, 5.00Hz, 2H) 4.63 (dt, J=47.56, 4.88 Hz, 2H) 6.41 (td, J=8.57, 2.50 Hz, 1H)6.62 (dd, J=12.62, 2.38 Hz, 1H) 7.82 (dd, J=8.90, 7.07 Hz, 1H) 8.05 (t,J=4.82 Hz, 1H)

tert-butyl 4-fluoro-2-[(3-fluoropropyl)amino]benzoate

ESI(+) MS: m/z 272 (MH⁺).

tert-butyl 4-fluoro-2-[(1-methoxy-2-methylpropan-2-yl)amino]benzoate

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 1.34 (s, 6H) 1.53 (s, 9H) 3.33 (br.s., 3H) 3.40 (s, 2H) 6.31-6.39 (m, 1H) 6.67 (dd, J=13.29, 2.44 Hz, 1H)7.82 (dd, J=8.84, 7.38 Hz, 1H) 8.22 (s, 1H)

Preparation of4-fluoro-2-[((S)-2-methoxy-1-methyl-ethyl)-(2,2,2-trifluoro-acetyl)-amino]-benzoicacid tert-butyl ester

A solution of 4-fluoro-2-((S)-2-methoxy-1-methyl-ethylamino)-benzoicacid tert-butyl ester (1.54 g, 5.44 mmol) in dichloromethane (30 mL) wascooled to 0°-5° C. Triethylamine (1.11 mL, 8.16 mmol) andtrifluoroacetic anhydride (1.15 mL, 8.16 mmol) were added. After 3 hoursat 0°-5° C. the mixture was washed with NaHCO₃ satured solution, waterand brine. The organic layer was dried over sodium sulfate, filtered andevaporated to give the title compound as yellowish oil (2 g, 99%).

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): (mixture of tautomers) 8.07 (m, 1H),7.53 (m, 1H), 7.29 (dd, J1=9.39 Hz, J2=2.68 Hz, 1H), 4.83 (m, 1H), 3.44(m, 1H), 3.30 (s, 3H), 1.49 (s, 9H), 0.86 (d, 3H).

Operating in a way analogous to that described above, the followingcompounds were obtained:

4-Fluoro-2-[((R)-2-methoxy-1-methyl-ethyl)-(2,2,2-trifluoro-acetyl)-amino]-benzoicacid tert-butyl ester

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): (mixture of tautomers) 8.07 (m, 1H),7.53 (m, 1H), 7.29 (dd, J1=9.39 Hz, J2=2.68 Hz, 1H), 4.83 (m, 1H), 3.44(m, 1H), 3.30 (s, 3H), 1.49 (s, 9H), 0.86 (d, 3H).

4-Fluoro-2-[(2-methoxy-ethyl)-(2,2,2-trifluoro-acetyl)-amino]-benzoicacid tert-butyl ester

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 8.07 (m, 1H), 7.50 (m, 1H), 7.41(dd, J1=9.39 Hz, J2=2.56 Hz, 1H), 4.28 (m, 1H), 3.55 (m, 1H), 3.46 (m,1H), 3.38 (m, 1H), 3.18 (s, 3H), 1.49 (s, 9H).

tert-butyl 4-fluoro-2-[(3-methoxypropyl)trifluoroacetyl)amino]benzoate

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 1.48 (s, 9H) 1.68-1.83 (m, 2H) 3.18(s, 3H) 3.21-3.29 (m, 1H) 3.33-3.38 (m, 2H) 4.06-4.18 (m, 1H) 7.46-7.52(m, 1H) 7.56 (dd, J=9.27, 2.68 Hz, 1H) 8.06 (dd, J=8.84, 6.40 Hz, 1H)

tert-butyl 4-fluoro-2-[(2-fluoroethyl)(trifluoroacetyl)amino]benzoate

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 1.50 (s, 9H) 3.54-3.74 (m, 1H)4.26-4.45 (m, 1H) 4.50-4.80 (m, 2H) 7.47-7.55 (m, 2H) 8.08 (dd, J=9.27,6.46 Hz, 1H)

tert-butyl 4-fluoro-2-[(3-fluoropropyl)(trifluoroacetyl)amino]benzoate

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 1.50 (s, 9H) 1.80-2.07 (m, 2H)3.26-3.42 (m, 1H) 4.21 (ddd, J=13.78, 8.90, 6.71 Hz, 1H) 4.42-4.60 (m,2H) 7.48-7.55 (m, 1H) 7.60 (dd, J=9.27, 2.44 Hz, 1H) 8.09 (dd, J=8.84,6.40 Hz, 1H)

tert-butyl4-fluoro-2-[(1-methoxy-2-methylpropan-2-yl)(trifluoroacetyl)amino]benzoate

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 1.09 (s, 3H) 1.47 (s, 3H) 1.52 (s,9H) 3.17 (s, 3H) 3.19 (d, J=9.75 Hz, 1H) 3.80 (d, J=9.63 Hz, 1H) 7.36(dd, J=9.45, 2.62 Hz, 1H) 7.47 (td, J=8.41, 2.68 Hz, 1H) 7.93 (dd,J=8.78, 6.46 Hz, 1H)

Preparation of2-[((S)-2-methoxy-1-methyl-ethyl)-(2,2,2-trifluoro-acetyl)-amino]-4-(4-methyl-piperazin-1-yl)-benzoicacid tert-butyl ester

A solution of4-fluoro-2-[((S)-2-methoxy-1-methyl-ethyl)-(2,2,2-trifluoro-acetyl)-amino]-benzoicacid tert-butyl ester (2 g, 5.28 mmol) and N-methylpiperazine (5.86 mL,52.8 mmol) in tetrahydrofuran (20 mL) was stirred at 60° C. for 7 days.The solution was then evaporated, NaHCO₃ satured solution was added andthe mixture extracted with dichloromethane (3 times). The organic layerwas washed with water, brine, dried over sodium sulfate filtered andevaporated to obtain a crude, which was purified by columnchromatography on silica gel (dichloromethane-methanol 93:7). The titlecompound (2.04 g, 84%) was obtained as yellowish solid.

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): (mixture of tautomers) 7.81 (d,J=9.15 Hz, 1H), 7.06 (dd, J1=9.15 Hz, J2=2.56 Hz, 1H), 6.79 (d, J=2.56Hz, 1H), 4.80 (m, 1H), 3.39 (m, 2H), 3.34-3.28 (m, 7H), 2.55 (m, 4H),2.29 (bs, 3H), 1.46 (s, 9H), 0.83 (d, 3H).

Operating in a way analogous to that described above, the followingcompounds were obtained:

2-[((R)-2-Methoxy-1-methyl-ethyl)-(2,2,2-trifluoro-acetyl)-amino]-4-(4-methyl-piperazin-1-yl)-benzoicacid tert-butyl ester

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): (mixture of tautomers) 7.81 (d,J=9.15 Hz, 1H), 7.06 (dd, J1=9.15 Hz, J2=2.56 Hz, 1H), 6.79 (d, J=2.56Hz, 1H), 4.80 (m, 1H), 3.39 (m, 2H), 3.34-3.28 (m, 7H), 2.55 (m, 4H),2.29 (bs, 3H), 1.46 (s, 9H), 0.83 (d, 3H).

2-[(2-Methoxy-ethyl)-(2,2,2-trifluoro-acetyl-amino]-4-(4-methyl-piperazin-1-yl)-benzoicacid tert-butyl ester

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): (mixture of tautomers) 7.83 (d,J=9.02 Hz, 1H), 7.05 (dd, J1=9.02 Hz, J2=2.68 Hz, 1H), 6.86 (d, J=2.68Hz, 1H), 4.31 (m, 1H), 3.55 (m, 1H), 3.40 (m, 1H), 3.32 (m, 4H), 3.25(m, 1H), 3.21 (s, 1H), 2.44 (t, J=5.12 Hz, 4H), 2.22 (bs, 3H), 1.46 (s,9H).

4-[(2-Dimethylamino-ethyl)-methyl-amino]-2-[(2-methoxy-ethyl)-(2,2,2-trifluoro-acetyl)-amino]-benzoicacid tert-butyl ester

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 7.81 (d, J=8.9 Hz, 1H), 6.78 (dd,J1=8.9 Hz, J2=2.8 Hz, 1H), 6.60 (d, J=2.8 Hz, 1H), 4.40-4.31 (m, 1H),3.59-3.39 (m, 4H), 3.23 (s, 3H), 3.22-3.15 (m, 1H), 3.00 (s, 3H), 2.40(m, 2H), 2.19 (bs, 6H), 1.46 (s, 9H).

tert-butyl2-[(3-methoxypropyl)(trifluoroacetyl)amino]-4-(4-methylpiperazin-1-yl)benzoate

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 1.45 (s, 9H) 1.68-1.84 (m, 2H) 2.26(br. s., 3H) 2.44-2.60 (m, 4H) 3.12-3.23 (m, 1H) 3.18 (s, 3H) 3.25-3.48(m, 6H) 4.08 (d, J=22.92 Hz, 1H) 6.92 (d, J=2.19 Hz, 1H) 7.02 (dd,J=9.02, 2.44 Hz, 1H) 7.81 (d, J=9.02 Hz, 1H)

tert-butyl2-[(2-fluoroethyl)(trifluoroacetyl)amino]-4-(4-methylpiperazin-1-yl)benzoate

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 1.46 (s, 9H) 2.22 (s, 3H) 2.43 (t,J=4.76 Hz, 4H) 3.25-3.31 (m, 4H) 3.41-3.59 (m, 1H) 4.27-4.46 (m, 1H)4.46-4.78 (m, 2H) 6.90 (d, J=2.07 Hz, 1H) 7.05 (dd, J=9.02, 2.68 Hz, 1H)7.83 (d, J=9.02 Hz, 1H)

tert-butyl2-[(3-fluoropropyl)(trifluoroacetyl)amino]-4-(4-methylpiperazin-1-yl)benzoate

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 1.46 (s, 9H) 1.80-2.05 (m, 2H) 2.25(br. s., 3H) 2.46 (br. s., 4H) 3.18-3.37 (m, 5H) 4.10-4.24 (m, 1H)4.38-4.60 (m, 2H) 6.95 (d, J=2.44 Hz, 1H) 7.04 (dd, J=8.96, 2.62 Hz, 1H)7.84 (d, J=9.02 Hz, 1H)

tert-butyl2-[(1-methoxy-2-methylpropan-2-yl)(trifluoroacetyl)amino]-4-(4-methylpiperazin-1-yl)benzoate

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 1.04 (s, 3H) 1.45 (s, 3H) 1.49 (s,9H) 2.22 (s, 3H) 2.44 (t, J=4.94 Hz, 4H) 3.20 (d, J=9.51 Hz, 1H) 3.23(s, 3H) 3.25-3.30 (m, 4H) 3.93 (d, J=9.51 Hz, 1H) 6.89 (d, J=2.32 Hz,1H) 7.00 (dd, J=8.96, 2.62 Hz, 1H) 7.70 (d, J=8.90 Hz, 1H)

Preparation of2-[((S)-2-methoxy-1-methyl-ethyl)-(2,2,2-trifluoro-acetyl)-amino]-4-(4-methyl-piperazin-1-yl)-benzoicacid trifluoroacetate

To a solution of2-[((S)-2-methoxy-1-methyl-ethyl)-(2,2,2-trifluoro-acetyl)-amino]-4-(4-methyl-piperazin-1-yl)-benzoicacid tert-butyl ester (2.03 g, 4.42 mmol) in dichloromethane (15 mL)trifluoroacetic acid (3.4 mL, 44.2 mmol) was added. The mixture wasstirred at room temperature for 15 hours then the solution wasevaporated to dryness affording the title compound as oil that was usedfor the next step without any further purification.

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): (mixture of tautomers) 12.10 (bs,1H), 9.74 (bs, 1H), 7.90 (d, J=8.90 Hz, 1H), 7.15 (dd, J1=8.90 Hz,J2=2.56 Hz, 1H), 6.89 (d, J=2.56 Hz, 1H), 4.76 (m, 1H), 4.03 (t, 2H),3.55 (m, 2H), 3.37 (m, 2H), 3.30 (s, 3H), 3.18 (m, 2H), 2.88 (bs, 3H),0.85 (d, 3H).

Operating in a way analogous to that described above, the followingcompounds were obtained:

2-[((R)-2-Methoxy-1-methyl-ethyl)-(2,2,2-trifluoro-acetyl)-amino]-4-(4-methyl-piperazin-1-yl)-benzoicacid trifluoroacetate

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): (mixture of tautomers) 12.10 (bs,1H), 9.74 (bs, 1H), 7.90 (d, J=8.90 Hz, 1H), 7.15 (dd, J1=8.90 Hz,J2=2.56 Hz, 1H), 6.89 (d, J=2.56 Hz, 1H), 4.76 (m, 1H), 4.03 (t, 2H),3.55 (m, 2H), 3.37 (m, 2H), 3.30 (s, 3H), 3.18 (m, 2H), 2.88 (bs, 3H),0.85 (d, 3H).

2-[(2-Methoxy-ethyl)-(2,2,2-trifluoro-acetyl)-amino]-4-(4-methyl-piperazin-1-yl)-benzoicacid trifluoroacetate

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): (mixture of tautomers) 12.76 (bs,1H), 9.73 (bs, 1H), 7.91 (d, J=8.78 Hz, 1H), 7.10 (dd, J1=8.78 Hz,J2=2.68 Hz, 1H), 7.01 (d, J=2.68 Hz, 1H), 4.15 (m, 1H), 4.04 (m, 2H),3.54 (m, 2H), 3.42 (m, 2H), 3.38 (m, 2H), 3.33 (m, 2H), 3.19 (s, 3H),3.14 (m, 2H), 2.86 (bs, 3H).

4-[(2-Dimethylamino-ethyl)-methyl-amino]-2-[(2-methoxy-ethyl)-(2,2,2-trifluoro-acetyl)-amino]-benzoicacid hydrochloride

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.59 (bs, 1H), 10.00 (bs, 1H), 7.88(d, J=8.9 Hz, 1H), 6.92 (dd, J1=8.9 Hz, J2=2.8 Hz, 1H), 6.74 (8d, J=2.8Hz, 1H), 4.18 (m, 1H), 3.79 (m, 2H), 3.56 (m, 1H), 3.47-3.36 (m, 2H),3.24 (m, 2H), 3.21 (s, 3H), 3.01 (s, 3H), 2.84 (bd, 6H).

2-[(3-methoxypropyl)(trifluoroacetyl)amino]-4-(4-methylpiperazin-1-yl)benzoicacid hydrochloride

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 1.70-1.81 (m, 2H) 2.84 (d, J=2.93Hz, 3H) 3.06-3.40 (m, 7H) 3.19 (s, 3H) 3.52 (d, J=10.36 Hz, 2H)3.96-4.06 (m, 1H) 4.09 (br. s., 2H) 7.07 (d, J=2.56 Hz, 1H) 7.10 (dd,J=8.90, 2.68 Hz, 1H) 7.93 (d, J=8.78 Hz, 1H) 10.27 (br. s., 1H) 12.76(br. s., 1H)

2-[(2-fluoroethyl)(trifluoroacetyl)amino]-4-(4-methylpiperazin-1-yl)benzoicacid hydrochloride

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 2.84 (br. s., 3H) 3.04-3.30 (m, 4H)3.47-3.56 (m, 2H) 3.54-3.67 (m, 1H) 4.06 (d, 2H) 4.18-4.40 (m, 1H)4.46-4.79 (m, 2H) 7.07 (d, J=2.19 Hz, 1H) 7.12 (dd, J=8.96, 2.62 Hz, 1H)7.91-7.97 (m, 1H) 10.33 (br. s., 1H) 12.83 (br. s., 1H)

2-[(3-fluoropropyl)(trifluoroacetyl)amino]-4-(4-methylpiperazin-1-yl)benzoicacid trifluoroacetate

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 1.82-2.02 (m, 2H) 2.87 (s, 3H) 3.14(m, 5H) 3.44 (m) 4.09 (m, 3H) 4.40-4.59 (m, 2H) 7.08-7.15 (m, 2H) 7.95(d, J=9.15 Hz, 1H) 9.72 (br. s., 1H) 12.81 (br. s., 1H)

2-[(1-methoxy-2-methylpropan-2-yl)(trifluoroacetyl)amino]-4-(4-methylpiperazin-1-yl)benzoicacid hydrochloride

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 1.07 (s, 3H) 1.43 (s, 3H) 2.84 (s,3H) 3.10-3.38 (m, 5H) 3.25 (s, 3H) 3.47-3.57 (m, 2H) 3.92 (d, J=9.51 Hz,1H) 3.95-4.02 (m, 2H) 7.00 (d, J=2.44 Hz, 1H) 7.10 (dd, J=8.84, 2.50 Hz,1H) 7.84 (d, J=8.78 Hz, 1H) 10.25 (br. s., 1H) 12.77 (br. s., 1H)

Example 23 Preparation of tert-butyl4-(4-acetylpiperazin-1-yl)-2-nitrobenzoate

To a solution of tert-butyl 2-amino-4-(piperazin-1-yl)benzoate (7.6 g,24.7 mmol) in dichloromethane (120 mL), triethylamine (13.46 mL, 98.7mmol) and trifluoroacetic anhydride (6.87 mL, 49.35 mmol) were added.After 1 hour the volatiles were evaporated and the crude was purified bycolumn chromatography (EtOAc/hexane 3:7) affording 9.46 gr (yield 95%)of the title compound.

ESI(+) MS: m/z 404 (MH⁺).

Example 24 Preparation of tert-butyl4-(4-methylpiperazin-1-yl)-2-(phenylamino)benzoate

In a dry Schlenk tube under argon atmosphere tert-butyl2-amino-4-(4-methylpiperazin-1-yl)benzoate (800 mg, 2.745 mmol) wasdissolved in dry toluene (14 mL). Argon was bubbled through the mixturefor a few minutes before adding bromobenzene (0.32 mL, 3.02 mmol, 1.1eq), Cs₂CO₂ (1.34 g, 4.118 mmol, 1.5 eq), Pd(OAc)₂ (16 mg, 0.069 mmol,2.5 mol %) and Rac-BINAP (88 mg, 0.137 mmol, 5 mol %). The mixture wasthen stirred at 100° C. for 21 hours. The mixture was allowed to cool toroom temperature and diluted with dichloromethane. Salts were filteredover a Celite pad and the filtrate was concentrated under reducedpressure. The crude product was purified by chromatography over silicagel (DCM/EtOH/NH₃ 7% in methanol 95:5:0.5) to give 1.13 g of titlecompound (quant. yield) as off-white solid

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 1.54 (s, 9H) 2.21 (s, 3H) 2.37-2.43(m, 4H) 3.15-3.20 (m, 4H) 6.43 (dd, J=9.15, 2.44 Hz, 1H) 6.60 (d, J=2.44Hz, 1H) 7.02-7.07 (m, 1H) 7.23-7.27 (m, 2H) 7.33-7.38 (m, 2H) 7.69 (d,J=9.02 Hz, 1H) 9.50 (s, 1H)

Example 25 Preparation of methyl2-methoxy-4-(4-methylpiperazin-1-yl)benzoate

Methyl 2-methoxy-4-fluoro-benzoate (1.6 gr, 9.7 mmol), K₂CO₃ (1.3 gr,9.7 mmol) and N-methyl piperazine (1.3 mL, 11.7 mmol) were heated at100° C. in DMSO (5 mL) for 20 hours. Reaction mixture was diluted withDCM and washed with water. Organic phase was dried over sodium sulfateand evaporated to dryness. Column chromatography purification on silicagel using dichloromethane/methanol 95:5 as the eluant, afforded 1.7 g(yield 66%) of the title compound.

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 2.25 (s, 3H) 2.45 (br. s., 4H)3.26-3.34 (m, 4H) 3.70 (s, 3H) 3.80 (s, 3H) 6.49 (d, J=2.32 Hz, 1H) 6.53(dd, J=8.84, 2.38 Hz, 1H) 7.61 (d, J=8.78 Hz, 1H)

Preparation of 2-methoxy-4-(4-methylpiperazin-1-yl)benzoic acidhydrochloride

Methyl 2-methoxy-4-(4-methylpiperazin-1-yl)benzoate (1.9 gr, 7.2 mmol)was heated at 40° C. in a mixture 2N NaOH (10 mL) and MeOH (10 mL) for 2hours. MeOH was evaporated and the acqueous layer was acidified to pH=6with 25% HCl and extracted with n-BuOH. Organic phase was dried oversodium sulfate and evaporated to dryness. affording 1.0 g (yield 61%) ofthe title compound.

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 2.82 (br. s., 3H) 2.99-3.31 (m, 4H)3.47 (br. s., 2H) 3.83 (s, 3H) 4.04 (br. s., 2H) 6.61 (d, 1H) 6.59 (s,1H) 7.66 (d, J=8.78 Hz, 1H) 10.49 (br. s., 1H) 11.91 (br. s., 1H)

Example 26 Preparation of 4-(4-methyl-piperazin-1-yl)-2-nitro benzoicacid hydrochloride

A mixture of 4-(4-methyl-piperazin-1-yl)-2-nitro-benzoic acid tert-butylester (16.4 g, 51 mmol) and 37% HCl (100 mL) in 1,4-dioxane (200 mL) wasstirred at room temperature for 4 hours. The resulting solid wasfiltered, washed thoroughly with 1,4-dioxane and dried under vacuum at45° C. The title compound was obtained as a pale yellow solid (13.45 g,87.5% yield), and it was used in the next step without any furtherpurification.

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 10.27 (bs, 1H), 7.81 (d, J=8.90 Hz,1H), 7.40 (d, J=2.69 Hz, 1H), 7.24 (dd, J1=8.90 Hz, J2=2.69 Hz, 1H),4.13 (bs, 2H), 3.55-3.06 (bs, 6H), 2.83 (s, 3H).

Operating in an analogous way, the following compounds were obtained:

4-[(3-Dimethylamino-propyl)-methyl-amino]-2-nitro-benzoic acidhydrochloride

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 13.07 (bs, 1H), 9.72 (bs, 1H), 7.76(d, J=9.0 Hz, 1H), 7.03 (d, J=2.6 Hz, 1H), 6.93 (dd, J1=9.0 Hz, J2=2.6Hz, 111), 3.51 (m, 2H), 3.08 (m, 2H), 3.03 (s, 3H), 2.77 (s, 6H), 1.90(m, 2H).

1. A method for treating a patient having cancer, comprisingadministering to said patient an effective amount ofN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide,or a pharmaceutically acceptable salt thereof, and an effective amountof at least one second therapeutic agent, wherein said at least onesecond therapeutic agent is selected from antihormonal agents,antiestrogens, antiandrogens, aromatase inhibitors, topoisomerase Iinhibitors, topoisomerase II inhibitors, agents that targetmicrotubules, platin-based agents, alkylating agents, DNA damagingagents, DNA intercalating agents, antineoplastic antimetabolites, kinaseinhibitors, anti-angiogenic agents, inhibitors of kinesins, therapeuticmonoclonal antibodies, mTOR inhibitors, histone deacetylase inhibitors,farnesyl transferase inhibitors, and hypoxic response inhibitors.
 2. Themethod of claim 1, wherein said cancer is selected from breast cancer,lung cancer, non-small cell lung cancer, colorectal cancer, prostatecancer, ovarian cancer, endometrial cancer, gastric cancer, clear cellrenal cell carcinoma, uveal melanoma, multiple myeloma,rhabdomyosarcoma, Ewing's sarcoma, Kaposi's sarcoma, medulloblastoma,anaplastic large cell lymphoma, neuroblastoma, rhabdomyosarcoma,glioblastoma, inflammatory myofibroblastic tumor, melanoma, Ewingssarcomas, retinoblastoma, squamous cell carcinoma, seminoma,teratocarcinoma, xeroderma pigmentosum, and thyroid follicular cancer.3. The method of claims 1 and 2, wherein said cancer selected frombreast cancer, non-small cell lung cancer, colorectal cancer, prostatecancer, neuroblastoma, melanoma and glioblastoma.
 4. The method of claim3, wherein said cancer is selected from non-small cell lung cancer,colorectal cancer, neuroblastoma, melanoma and glioblastoma.
 5. Themethod of claim 4, wherein said cancer is non-small cell lung cancer. 6.The method of claim 4, wherein said cancer is colorectal cancer.
 7. Themethod of claim 4, wherein said cancer is neuroblastoma.
 8. The methodof claim 4, wherein said cancer is melanoma.
 9. The method of claim 4,wherein said cancer is glioblastoma.
 10. The method of claim 1, whereinsaidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide,or a pharmaceutically acceptable salt thereof, and said at least onesecond therapeutic agent are simultaneously administered to saidpatient.
 11. The method of claim 1, wherein saidN-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide,or a pharmaceutically acceptable salt thereof, and said at least onesecond therapeutic agent are sequentially administered to said patient.12. The method according to claim 1, wherein said at least one secondtherapeutic agent is selected from kinase inhibitors.
 13. The methodaccording to claim 12, wherein said cancer is selected from breastcancer, lung cancer, non-small cell lung cancer, colorectal cancer,prostate cancer, ovarian cancer, endometrial cancer, gastric cancer,clear cell renal cell carcinoma, uveal melanoma, multiple myeloma,rhabdomyosarcoma, Ewing's sarcoma, Kaposi's sarcoma, medulloblastoma,anaplastic large cell lymphoma, neuroblastoma, rhabdomyosarcoma,glioblastoma, inflammatory myofibroblastic tumor, melanoma, Ewingssarcomas, retinoblastoma, squamous cell carcinoma, seminoma,teratocarcinoma, xeroderma pigmentosum, and thyroid follicular cancer.14. The method of claims 12 and 13, wherein said cancer is selected frombreast cancer, non-small cell lung cancer, colorectal cancer, prostatecancer, neuroblastoma, melanoma and glioblastoma.
 15. The method ofclaim 14, wherein said cancer is selected from non-small cell lungcancer, colorectal cancer, neuroblastoma, melanoma and glioblastoma. 16.The method of claim 15, wherein said cancer is non-small cell lungcancer.
 17. The method of claim 15, wherein said cancer is colorectalcancer.
 18. The method of claim 15, wherein said cancer isneuroblastoma.
 19. The method of claim 15, wherein said cancer ismelanoma.
 20. The method of claim 15, wherein said cancer isglioblastoma.